Copper-mediated C-H cyanation of (hetero)arenes with ethyl (ethoxymethylene)cyanoacetate as a cyanating agent

Article abstract of DOI:10.1039/c7cc03384b

A copper-mediated direct C-H cyanation of (hetero)arenes with ethyl (ethoxymethylene)cyanoacetate as a safe cyanating agent has been successfully developed by using molecular oxygen as the oxidant. The reaction tolerates a variety of functional groups and provides a facile and efficient method for the synthesis of a wide range of (hetero)aryl nitriles.

Full text of DOI:10.1039/c7cc03384b

Showcasing research from Chaorong Qi and Huanfeng Jiang’s
laboratory, Key Lab of Functional Molecular Engineering of
Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, P. R. China.
As featured in:
Copper-mediated C–H cyanation of (hetero)arenes with ethyl
(ethoxymethylene)cyanoacetate as a cyanating agent
A copper-mediated direct C–H cyanation of (hetero)arenes with
ethyl (ethoxymethylene)cyanoacetate as a safe cyanating agent
has been successfully developed by using molecular oxygen as
the oxidant. The reaction tolerates a variety of functional groups
and provides a facile and efficient method for the synthesis of a
wide range of (hetero)aryl nitriles.
See Chaorong Qi,
Huanfeng Jiang et al.,
Chem. Commun., 2017, 53, 7994.
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Copper-mediated C–H cyanation of (hetero)arenes
with ethyl (ethoxymethylene)cyanoacetate as a
cyanating agent†
Cite this: Chem. Commun., 2017,
53, 7994
Received 2nd May 2017,
Accepted 6th June 2017
ab
a
Chaorong Qi,
*
Xiaohan Hua and Huanfeng Jiang
*
DOI: 10.1039/c7cc03384b
rsc.li/chemcomm
A copper-mediated direct C–H cyanation of (hetero)arenes with
ethyl (ethoxymethylene)cyanoacetate as a safe cyanating agent has
been successfully developed by using molecular oxygen as the
oxidant. The reaction tolerates a variety of functional groups and
provides a facile and efficient method for the synthesis of a wide
range of (hetero)aryl nitriles.
Aryl nitriles are a class of important compounds because they
are key units of numerous natural products, agrochemicals,
and pharmaceuticals, such as rilpivirine, escitalopram and
neratinib (Fig. 1).1 In addition, they find versatile applications
in organic synthesis as precursors since the nitrile group can be
readily transformed into various functional groups, such as
amides, amines, amidines, aldehydes and carboxylic acids, etc.2
Traditionally, these important compounds can be prepared
by the Sandmeyer3 (Scheme 1a) and the Rosenmund–von Braun
reactions (Scheme 1b),4 both of which require stoichiometric
amounts of toxic CuCN as the cyano source and harsh reaction
conditions. In the past decades, great efforts have been made to
develop new and efficient methods for the synthesis of different
aryl nitriles, mainly through transition metal-catalyzed cyanation
Fig. 1 Representative important nitrile-containing molecules.
of aryl (pseudo)halides and chelation-assisted C–H bond cyanation several combined ‘‘CN’’ sources, such as NH3(aq)/DMF,17a
of (hetero)arene (Scheme 1c).5 Many metal cyanides, such as NH4HCO3/DMSO,17b NH4HCO3/DMF,17c and NH4I/DMF17d were
CuCN,6 NaCN,7 Zn(CN)2,8 and K4[Fe(CN)6],9 have been successfully also reported for the cyanation of various substrates under
developed as the cyano-group source for these processes. On the different reaction conditions. Although significant progress has
other hand, a range of nonmetallic cyanating agents have also been made in this research field, the development of new and
been exploited for the construction of aryl nitriles in recent years, more practical methods for the synthesis of aryl nitriles,
including acetone cyanohydin,10 nitromethane,11 acetonitrile,12 especially via noble-metal-free C–H cyanation of (hetero)arene
malononitrile,13 N-cyano-N-phenyl-p-toluenesulfonamide (NCTS),14 using nontoxic and easily available cyano sources, is still highly
N,N-dimethylformamide (DMF),15 and benzyl cyanide.16 Moreover, desirable.
Recently, we disclosed that ethyl (ethoxymethylene)cyanoacetate,
a versatile building block in organic synthesis,18 could be used
as a raw material for the synthesis of 2,2,4-trisubstituted 3(2H)-
furanones.19a And subsequently, we investigated the cyanation of
aryl boronic acids and aryl iodides with ethyl (ethoxymethylene)-
cyanoacetate as a cyanating agent for the synthesis of aryl
nitriles.19b Enlightened by these interesting works, we envisioned
a copper-mediated direct C–H bond cyanation of (heter)arenes by
a Key Lab of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China. E-mail: crqi@scut.edu.cn, jianghf@scut.edu.cn
b State Key Lab of Luminescent Materials and Devices, South China University of
Technology, Guangzhou 510640, P. R. China
† Electronic supplementary information (ESI) available: Details of experimental
procedure, compound characterization data and copies of 1H and 13C NMR
spectra. See DOI: 10.1039/c7cc03384b
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Table 1 Optimization of the reactiona
Entry
[Cu] (equiv.)
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
CuI (1)
CuBr (1)
TBHP (2 equiv.)
TBHP (2 equiv.)
TBHP (2 equiv.)
TBHP (2 equiv.)
DTBP (2 equiv.)
H2O2 (2 equiv.)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
DMF
DMF
DMF
15
39
30
76
Cu(NO3)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (2)
Cu(OAc)2 (0.5)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
—
57
38
73c
8d
9d
10d
11d
12d
13d
14d
15d
16e
90 (81)
60
13
51
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
Air (1 atm)
N.D.
N.D.
N.D.
Trace
N.D.
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Scheme 1 Strategies for the synthesis of aryl nitriles.
O2 (1 atm)
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), solvent (2 mL),
130 1C, 24 h. b Yields were determined by GC-MS analysis with n-dodecane
as internal standard; number in parentheses is the yield of isolated product.
using ethyl (ethoxymethylene)cyanoacetate as a safe cyanating
agent, which would provide a facile and efficient method for the
c
Dicyanated product 2-(pyridin-2-yl)isophthalonitrile was obtained in 22%
e
yield. d The reaction was performed with 1.2 equiv. of 2a for 12 h. In the
synthesis of a range of (hetero)aryl nitriles (Scheme 1d). Herein, absence of 2a.
we report our results in details.
Initially, 2-phenylpyridine (1a) was chosen as the model
With the optimized conditions in hand, we then examined
substrate for the optimization of the reaction conditions, and the substrate scope and limitation of our new protocol with
the results are summarized in Table 1. On the basis of the various 2-arylpyridines. As can be seen from Scheme 2, a wide
conditions we previously optimized for the cyanation of aryl range of 2-arylpyridines bearing either electron-donating or
boronic acids and aryl iodides,19b 1a was first treated with electron-withdrawing groups at the para-position of the aryl ring,
t
2 equiv. of 2a in the presence of 1 equiv. of CuI and 2 equiv. including alkyl (Me, Et and Bu), methoxy, halide (F and Br),
of TBHP in DMF at 130 1C for 24 h, but the desired product 3aa trifluoromethyl, and cyano groups, could undergo the reaction
was only formed in 15% yield (entry 1). To our delight, smoothly to deliver the monocyanated products (3b–3i) in moderate
replacement of CuI with Cu(OAc)2 dramatically increased the to high yields. The ortho-substituted substrates also worked well to
yield of 3aa while other copper salts showed low activity (entries give the desired products (3j–3l) in 65–81% yields. Notably, the
2–4). The oxidant also has a great impact on the reaction. The reaction of 2-arylpyridines with a substituent at the meta-position of
reaction could take place when DTBP or H2O2 was used as the the benzene ring could react with 2a regioselectively, affording the
oxidant instead of TBHP, but low yields of 3aa were obtained less hindered ortho-cyanated products 3m–3o in excellent yields, and
(entries 5 and 6). In contrast, molecular oxygen could give 3aa no regioisomeric products were detected. More importantly, our
in a high yield although dicyanated product, 2-(pyridin-2- protocol could be applied to the cyanation of heterocyclic C–H bond.
yl)isophthalonitrile, was also formed in 22% yield in this case For example, 2-(thiophen-2-yl)pyridine (1p) could be cyanated
(entry 7). Considering that O2 is a cheaper and greener oxidant exclusively at the 2-position of thienyl moiety to give the expected
than TBHP, we decided to further optimize other reaction product 3p in a high yield.
parameters under 1 atm of O2. To our delight, by reducing
Subsequently, we examined a variety of nitrogen containing
the equivalents of 2a to 1.2 equiv. and shortening the reaction chelating groups under the optimal copper-mediated cyanation
time to 12 h, the desired product 3aa was obtained as the sole conditions (Scheme 3). Gratifyingly, 2-arylpyridines bearing a
product in an excellent yield (entry 8). Both increasing or substituent at the 3- and 5-position of the pyridyl ring were able
decreasing the amount of Cu(OAc)2 would lead to the decrease to undergo smooth cyanation to give rise to the desired products
of the yield (entries 9 and 10). Further investigation revealed 5a–5e in excellent yields. However, the reaction of 6-methyl-2-
that the solvent also plays a crucial role in the transformation. phenylpyridine was sluggish and only trace amount of product 5f
DMF proved to be the most suitable media for the reaction was observed. This might be due to the steric effect of the methyl
while the use of other solvents, such as DMA, DMSO, and NMP, group, which would prevent the coordination of the pyridyl ring
resulted in low yield or no product (entries 8, 11–13). Finally, with copper salt to form an active complex. The replacement of
the control experiments confirmed that Cu(OAc)2, O2 and 2a are pyridine with other heterocycles, such as pyrimidine as the
all essential for the transformation (entries 14–16).
chelating group, also gave the cyanated products (5g and 5h)
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Scheme 3 Scope of chelating group. Reaction conditions: 4 (0.3 mmol),
2a (0.36 mmol), Cu(OAc)2 (0.3 mmol), O2 (1 atm), DMF (2 mL), 130 1C, 12 h.
Isolated yields based on 4.
Scheme 2 Substrate scope with respect to 2-arylpyridines. Reaction
conditions: 1 (0.3 mmol), 2a (0.36 mmol), Cu(OAc)2 (0.3 mmol), O2 (1 atm),
DMF (2 mL), 130 1C, 12 h. Isolated yields based on 1.
in satisfactory yields. Indole was readily cyanated at the C-2
position with high efficiency when pyrimidyl group was installed
as the chelating group (5i). In addition, 1-phenylpyrazole (4j) was
also a good reaction partner to give the cyanated product 5j in a
moderate yield although longer reaction time was required.
To obtain some insight into the mechanism of the reaction, a
series of control experiments were performed. Firstly, when CuCN
was used instead of Cu(OAc)2 and 2a during the reaction, only a
trace amount of 3a was found (Scheme 4a), indicating that the
reaction might not proceed via the CuCN intermediate, which
might be formed from Cu(OAc)2 and 2a.15a Secondly, it was
found that the present reaction could occur smoothly even in the
presence of 4 equiv. of the radical scavenger 2,2,6,6-teramethyl-1-
piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT)
(Scheme 4b), revealing that the reaction might not proceed through
Scheme 4 Mechanism studies.
a radical pathway. Moreover, substrate 1e did not undergo H/D implying that C–H bond cleavage might be involved in the rate-
exchange in the presence of CD3OD under the standard conditions limiting step. Finally, by using a picric acid strip, the in situ
(Scheme 4c). This result suggests that the C–H activation step generated cyanide anion could be detected. But it also should be
would be irreversible. In addition, the reaction exhibited inter- pointed out that both copper salt and oxygen are necessary for the
molecular kinetic isotope effect both in parallel reactions (kH/kD
=
formation of free cyanide anions from 2a (see Table S1, the ESI† for
4.6) and in competitive experiment (kH/kD = 4.0) (Scheme 4d), more details).
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reductive elimination of C affords product 3a along with CuOAc,
which is oxidized by O2 to regenerate Cu(OAc)2 to close the cycle.
In summary, we have developed a copper-mediated direct
cyanation of (hetero)arenes with ethyl (ethoxymethylene)-
cyanoacetate as a cyanating agent and molecular oxygen as the
oxidant, providing an efficient and practical method for the synthesis
of a range of (hetero)aryl nitriles. Various nitrogen containing
chelating groups could be employed for the reaction and a variety
of functional groups were well tolerated. Further investigation on the
reaction mechanism and the application of this strategy to the
synthesis of other nitriles are currently ongoing in our laboratory.
We thank the National Key Research and Development
Program of China (2016YFA0602900), the National Natural
Science Foundation of China (21572071 and 21420102003)
and the Fundamental Research Funds for the Central Univer-
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