An aerobic Cu-mediated practical approach to aromatic nitriles using cyanide anions as the nitrogen source

Article abstract of DOI:10.1039/c6ob01269h

A Cu-mediated cyanation of aryl methyl ketones using cyanide anions as the nitrogen source was achieved to provide aromatic nitriles in moderate to good yields. The reaction tolerates a variety of synthetically important functional groups.

Full text of DOI:10.1039/c6ob01269h

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An aerobic Cu-mediated practical approach to
aromatic nitriles using cyanide anions as the
nitrogen source†
Cite this: DOI: 10.1039/c6ob01269h
Received 12th June 2016,
Accepted 14th June 2016
Lijun Gu,*a Cheng Jin,b Hongtao Zhang,a Jiyan Liu,a Ganpeng Li*a and Zhi Yangc
DOI: 10.1039/c6ob01269h
www.rsc.org/obc
A Cu-mediated cyanation of aryl methyl ketones using cyanide coordinated cyanide anion (CN–) as the nitrogen source is
anions as the nitrogen source was achieved to provide aromatic more challenging because the negatively charged cyanide
nitriles in moderate to good yields. The reaction tolerates a variety anion is usually regarded as a pseudohalide and exists as an
of synthetically important functional groups.
integrated component in many chemical reactions. Very
recently, Lei and You developed a copper-catalyzed aerobic
conversion of the CvO bond of aldehydes to a CuN bond
using coordinated cyanide anions as the nitrogen source.9
Given the importance of aromatic nitriles, we disclose herein
our preliminary results on the copper-catalyzed conversion of
aromatic ketones to aromatic nitriles using coordinated
cyanide anions as the nitrogen source in the presence of mole-
cular oxygen. The protocol involves the cleavage of the C(CO)–
C(α) single bond of ketones and the CuN triple bond of the
cyanide anion (Scheme 1).
We started our investigation on ketone nitrogenation
employing acetophenone 1a as a model substrate. Specifically,
treatment of acetophenone 1a with CuCN at 150 °C for
14 hours under an oxygen atmosphere led to the formation of
the desired benzonitrile 2a in 76% yield (Table 1, entry 1).
Solvent screening revealed that DMF gave a lower yield (49%)
(Table 1, entry 2), while the other solvents studied such as
DCE, NMP and PhCF3 were all inferior in terms of the reaction
yield (Table 1, entries 3–5). Replacement of CuCN with the
CuBr2/K3[Fe(CN)6] system gave a comparable yield (61%)
(Table 1, entry 6). Changing CuCN to Cu(OAc)2/K3[Fe(CN)6],
CuCl2/K3[Fe(CN)6], CuCl/K3[Fe(CN)6] or CuBr/K3[Fe(CN)6]
diminished the reactivity (Table 1, entries 7–10). No desired
The nitrile group is a prevalent functional group in organic
synthesis.1 In particular, aromatic nitriles are a class of valu-
able compounds with numerous applications in various areas,
including pharmaceuticals, dyes, pesticides, and materials.2,3
In addition, aromatic nitriles are also potent intermediates in
fine chemical synthesis because the nitrile group can be easily
used for functional group transformations, including the for-
mation of amines, amides, acids, aldehydes and heterocycles.
As a result, the development of new methods used to prepare
aromatic nitriles has been intensively studied in synthetic
organic chemistry.
Traditional synthetic methods are the Sandmeyer reaction
and the Rosenmund–von Braun reaction.4 The nucleophilic
cyanation of aryl halides under transition metal catalysis with
cyanating agents has emerged as an alternative route to aryl
nitriles.5 Recently, transition-metal-catalyzed C–H bond
functionalization has enabled the direct cyanation of aromatic
C–H bonds.6 The cleavage of C–C single bonds in a selective
manner is a very important reaction in both academic research
and industrial applications. The chemoselective C(CO)–C(α)
bond cleavage of ketones is a fundamental reaction that has
been extensively studied.7 Very recently, the Guo group has
reported the copper-catalyzed aerobic synthesis of aromatic
nitriles from ketones via C(CO)–C(α) bond cleavage.8
Ammonium salts are used as the nitrogen source in the con-
version. However, in contrast to ammonium salts used as the
nitrogen source in the synthesis of aromatic nitriles, using a
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education Yunnan Minzu University, Kunming, Yunnan
650500, China. E-mail: gulijun2005@126.com, ganpeng_li@sina.com.cn
bNew United Group Company Limited, Changzhou, Jiangsu 213166, China
cYunnan Bai Yao Group Innovation and R&D Center, China
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ob01269h
Scheme 1 Synthetic route to aromatic nitriles using cyanide anions as
the nitrogen source.
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of aryl methyl ketonesa
Entry
Cyanide
Cu source
Solvent
Yieldb (%)
Entry
1
Ketone 1
Product 3
Yieldb (%)
71
1
2
3
4
5
6
7
8
None
None
None
None
CuCN
CuCN
CuCN
CuCN
CuCN
CuBr2
Cu(OAc)2
CuCl2
CuCl
DMSO
DMF
DCE
76
49
Trace
11
Trace
61
33
17
25
13
NMP
2
3
67
76
None
PhCF3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K3[Fe(CN)6]
K3[Fe(CN)6]
K3[Fe(CN)6]
K3[Fe(CN)6]
K3[Fe(CN)6]
None
9
10
11c
12d
CuBr
CuCN
CuCN
0
0
None
4
5
6
70
62
69
a Reaction conditions: 1a (0.5 mmol), Cu source (0.7 mmol), K3[Fe
(CN)6] (0.2 mmol), solvent (2 mL), 150 °C in O2 for 14 h. b Isolated
yield. c K2S2O8 was used as the oxidant, in Ar for 20 h. d Under an Ar
atmosphere.
benzonitrile 2a was obtained when K2S2O8 was used as the
oxidant (Table 1, entry 11). Reactions in the absence of an
oxygen atmosphere did not generate a detectable amount of
product 2a (Table 1, entry 12). The results imply that O2 is
crucial to the cyanation reaction.
With the optimized reaction conditions in hand, we went
on to explore the scope of the copper-promoted cyanation reac-
tion and found that the transformation was compatible with a
wide range of functional groups. Several substituted acetophe-
nones reacted smoothly with the CuCN/O2 system to generate
7
8
9
78
65
57
the corresponding aryl nitriles in moderate to good yields 10
under the optimized conditions (Table 2). Electron-donating
66
72
63
and electron-withdrawing groups on the aryl ring of the aryl
methyl ketone moiety were compatible with the reaction con-
11
ditions and halide substituents, such as F, Cl and Br, did not
12
13
affect the reactivity of the substrates. Substituents in the para-,
meta- or ortho-position of the phenyl ring were well tolerated.
For example, substrates 1e, 1g, and 1h with a Cl group were
transformed into products 2e, 2g, and 2h, respectively, in good
yield. Importantly, the polysubstituted derivative 1i gave the
desired product 2i in good yield. Aromatic methyl ketone 1j
with a naphthyl group also participated in this Cu-mediated
cyanation reaction, affording the desired product in 57% yield
(Table 2, entry 9). It is worth noting that the heteroaryl groups
worked well to afford the corresponding products in good
yield (Table 2, entries 10–13).
74
a Reaction conditions: 1a (0.5 mmol), CuCN (0.7 mmol), DMSO (2 mL),
150 °C in O2 for 14–16 h. b Isolated yield.
Highlighting the utility of this transformation, some repre- benzophenone did not deliver the corresponding nitrile under
sentative acetophenone derivatives were selected and subjected the same reaction conditions (Table 3, entries 3 and 4).
to the standard conditions. When α,β-unsaturated ketone was
In order to have some information on the reaction mechan-
employed as the substrate, the reaction proceeded smoothly ism of this cyanation process, some control experiments were
and gave the desired product in 61% yield (Table 3, entry 1). It carried out. It was found that 13C-DMSO instead of DMSO as
was found that aliphatic ketone 1p could also achieve this con- the solvent could not lead to the 13C-labelled product under
version (Table 3, entry 2). Unfortunately, propiophenone or standard conditions, which eliminated the possibility of the
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Table 3 Scope of ketonesa
Entry
1
Ketone 1
Product 3
Yieldb (%)
61
Scheme 3 Possible mechanism.
2
3
70
0
aldehyde may be involved in this process. When 5.0 equiva-
lents of TEMPO, a radical-trapping reagent, were added to the
reaction under standard conditions no desired product was
obtained, suggesting that free radical intermediates may be
involved in the reaction.
4
0
On the basis of these preliminary results and previous
studies,8,9 the catalytic cycle of this transformation was
hypothesized as shown in Scheme 3. Firstly, CuI is oxidized to
CuII under an O2 atmosphere.12 With the help of CuII and O2,
the substrate 1a is oxidized to give the corresponding benz-
aldehyde 3a via cleavage of the C–C bond. Subsequently, the
key intermediate A is formed through a single electron trans-
fer. At this stage, the reaction of intermediate A with CuCN
will give the CuI-bonded carbon-centered radical intermediate
B via the regioselectivity of C–N bond formation. The sub-
sequent aerobic oxidation of intermediate B generates species
C.13 At this juncture, the resulting CuII intermediate C will
produce benzoyl isocyanate D, which will decompose to give
benzonitrile 2a with extrusion of CO2 gas.
a Reaction conditions: 1a (0.5 mmol), CuCN (0.7 mmol), DMSO (2 mL),
150 °C in O2 for 16 h. b Isolated yield.
In summary, we have developed a Cu-mediated Csp2–Csp3
cleavage reaction toward the formation of aromatic nitriles,
using cyanide anions as the nitrogen source. A wide range of
functional groups were tolerated under the optimized reaction
conditions. In addition, molecular oxygen, the most environ-
mentally friendly oxidant, was employed at a pressure of 1
atmosphere. Due to the easy availability of the starting
materials and potential applications of the products, this
method is highly promising in organic synthesis. Mechanistic,
scope, and limitation studies of the reaction are in progress in
our laboratory.
Scheme 2 Experiments for mechanistic studies.
carbon atom in the cyano group derived from DMSO
(Scheme 2a). A 13C-labelled product was generated in 73%
yield using a 13C-carbonyl-labelled ketone 1n as the reagent,
which certainly excluded the deacylative cyanation reaction of
the aryl methyl ketone (Scheme 2b). The replacement of CuCN
with sodium cyanate resulted in a trace amount of benzo-
nitrile.10 Further GC-MS detection of the gas phase of the reac-
tion revealed that no NH3 was generated during the reaction.
The results indicate that the conversion of the CvO bond of
the aryl methyl ketone to a CuN bond via an imine intermedi-
ate, followed by oxidation of the imine to the nitrile could be
ruled out.
We are grateful for the financial support from the Program
for Innovative Research Team (in Science and Technology) in
the University of Yunnan Province (IRTSTYN 2014-11) and the
Applied Basic Research Key Project of Yunnan (2013FA039).
We supposed that methyl benzoate might be the intermedi-
ate. To probe this, methyl benzoate was treated under the stan-
dard reaction conditions. To our surprise, no desired product
was observed, which provided evidence that the reaction does
not proceed via an ester intermediate. It has been reported
that an aryl methyl ketone can be transformed into an aryl
aldehyde.11 Then, the aldehyde undergoes the cyanation reac-
tion to form a nitrile. Benzaldehyde 3a was subjected to the
optimized reaction conditions. The desired benzonitrile 2a
was obtained in 49% yield. The results indicate that benz-
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