Copper-catalyzed cyanation of aryl iodides using nitromethane

Article abstract of DOI:10.1246/cl.170798

The copper-catalyzed cyanation of aryl iodides is described using nitromethane as a CN source. In situ generation of a “CN” species from nitromethane is plausible. This strategy is an advantageous synthetic method for the construction of an aromatic CCN bond, because nitromethane is a common and easily handled compound that is readily available as a cyanation reagent, and its use allows the avoidance of using toxic metal cyanides.

Full text of DOI:10.1246/cl.170798

CL-170798
Received: August 22, 2017 | Accepted: September 15, 2017 | Web Released: September 23, 2017
Copper-catalyzed Cyanation of Aryl Iodides Using Nitromethane
#
#
Yohei Ogiwara, Hiromitsu Morishita, Minoru Sasaki, Hiroki Imai, and Norio Sakai*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510
(
E-mail: sakachem@rs.noda.tus.ac.jp)
The copper-catalyzed cyanation of aryl iodides is described
using nitromethane as a CN source. In situ generation of a
been used as cyanation reagents, even though the examples are
+
+
t
still limited: DMF/NH , DMSO/NH4 , HCONH , BuNC, etc.
4
2
6
“
CN” species from nitromethane is plausible. This strategy is
(Scheme 1B, eq 4). Nitromethane is also considered a poten-
tially valuable entry to the list of non-CN-containing cyanation
reagents because of its chemical stability and commercial
availability. However, the use of nitromethane as a cyano source
for catalytic aromatic C­CN bond formation is exceptionally
an advantageous synthetic method for the construction of an
aromatic C­CN bond, because nitromethane is a common and
easily handled compound that is readily available as a cyanation
reagent, and its use allows the avoidance of using toxic metal
cyanides.
7­9
rare. In this paper, we describe the copper-catalyzed cyanation
of aryl iodides using nitromethane as a cyanation reagent
(Scheme 1B, eq 5).
Keywords: Aromatic C–CN bond formation
|
Copper-catalyzed cyanation | Nitromethane
In 2015, our research group reported the copper-catalyzed
1
0
N-nitrosation of amines using nitromethane as a nitroso source.
Aromatic C­CN bond formation is one of the most
straightforward approaches for the construction of benzonitrile
derivatives, which make up an important class of structural
During the investigation of the substrate scope for nitrosation,
when a 2-iodoaniline derivative was used as a starting substrate,
two different products were obtained: the expected N-nitrosation
product (34%), and a further Ar­I cyanation product (25%)
(eq 6). The formation of the latter product indicated that
nitromethane could function as a cyanation reagent under those
conditions, which led to the development of catalytic cyanation
using nitromethane. A study for the optimization of cyanation
was then conducted using 4-methoxyiodobenzene (1a) as a
substrate (Table 1).
1
2
units in organic chemistry. The Sandmeyer reaction and the
3
Rosenmund-von Braun reaction are well-known classic meth-
ods for the synthesis of aryl nitriles (Scheme 1A, eq 1). In recent
decades, many researchers have contributed to significant
improvements in the cyanation procedure that have involved
transition-metal-catalyzed cross-coupling between aryl halides,
4
or pseudo-halides, with metal cyanides (Scheme 1A, eq 2).
These reactions remain the most reliable procedure for the
formation of aromatic C­CN bonds, but the use of stoichio-
metric amounts of toxic metal cyanides, copper cyanide in
particular, requires harsh reaction conditions. Cyanation using
metal-free organic cyanating reagents, therefore, is an alternative
and significant strategy to access aromatic nitriles, and elegant
examples have been developed using nitriles as cyanation
sources (Scheme 1B, eq 3).5 Recently, several organic com-
pounds that lack a cyano group in their molecular skeletons have
I
Cu(OTf)
DBU
2
(cat)
I
CN
+
H
NO
(1 atm)
, 90 °C
NO
NO
CH
2
3
2
(6)
N
N
N
Me
O
Me
Me
25%
34%
Table 1. Optimization of the reaction conditionsa
I
catalyst (20 mol %)
additive(s)
CN
3 2
CH NO , 100 °C, 24 h
MeO
MeO
1
a
2a
A. metal cyanides
Sandmeyer (X = N
+) and Rosenmund-von Braun (X = I) reactions
Yield/%b
2
Entry Catalyst
Additive(s)
X
CN
Ar
+
CuCN
Ar
Ar
(1)
(2)
1
2
3
4
5
6
Cu(OTf)2 DBU (1 equiv)
19
21
33
49
55
63
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DBU (1 equiv)
DMAP (1 equiv)
DMAP (2 equiv)
DMAP (1 equiv), NEt3 (1 equiv)
DMAP (1 equiv),
transition-metal-catalyzed coupling
X
CN
catalyst
Ar
+
MCN
B. organic compounds
nitriles as a CN source
X
CN
CN
N-methylpiperidine (1 equiv)
DMAP (1 equiv),
N-methylpiperidine (1 equiv)
DMAP (1 equiv),
N-methylpiperidine (1 equiv)
DMAP (1 equiv),
N-methylpiperidine (1 equiv)
DMAP (1 equiv),
catalyst
catalyst
Ar
+
RCN
Ar
(3)
(4)
7
8
9
0
CuCl
CuBr
CuI
64
64
56
0c
substrates without a CN group
X
Ar
+
CN source
Ar
(
CN source: DMF/NH +, DMSO/NH +
4
4
, HCONH
2
, tBuNC, etc)
nitrometane as a cyanation reagent (this work)
1
none
I
CN
[Cu] cat.
Ar
+
CH NO
Ar
(5)
N-methylpiperidine (1 equiv)
3
2
aReaction conditions: 1a (0.5 mmol), catalyst (0.1 mmol),
additive (0.5 mmol), CH3NO2 (0.5 mL, ca. 9.3 mmol), 100 °C,
24 h. GC yield. 18% conversion of 1a.
Scheme 1. Cyanation reagents in aromatic C­CN bond
formation.
b
c
1736 | Chem. Lett. 2017, 46, 1736–1739 | doi:10.1246/cl.170798
© 2017 The Chemical Society of Japan

Table 2. Copper-catalyzed cyanation of iodoarenesa
On the basis of our previous results, when the reaction of 1a
in the presence of a catalytic amount of Cu(OTf)2 and 1 equiv of
DBU was performed in nitromethane, as a solvent and a CN
source, at 100 °C for 24 h, the formation of the desired cyanation
product 2a was observed in 19% yield, as measured by GC
analysis (Entry 1). The use of CuBr2 gave a similar result
CuBr (20 mol %)
DMAP (1 equiv)
I
CN
N-methylpiperidine (1 equiv)
R
R
CH NO , 100 °C, 24 h
3
2
1
2
b
Entry
Iodoarene 1
Benzonitrile 2, Yield
(
Entry 2), but the use of 1 equiv or 2 equiv of DMAP, instead of
DBU, increased the yield to 33% and 49%, respectively (Entries
and 4). When a combination of 1 equiv each of DMAP and
I
CN
3
Z
Z
NEt was used as additives, the cyanation proceeded in a 55%
3
c
GC yield (Entry 5). After several further screenings, DMAP and
N-methylpiperidine was found to be the best additive pair for
this transformation (Entry 6). Though copper(I) catalysts such as
CuCl, CuBr, and CuI gave similar results (Entries 7­9), only an
1
2
1a, (Z = O)
1b, (Z = S)
2a, 70%
2b, 27%
I
CN
R
R
18% conversion of 1a (0% yield of 2a) could be determined in
the absence of a copper catalyst (Entry 10).
3
4
5
6
7
1c, (R = 2-Me)
1d, (R = 3-Me)
1e, (R = 4-Me)
2c, 63%
2d, 65%
2e, 59%
2f, 68%
Copper-catalyzed cyanation using nitromethane as solvent
and CN source was then conducted for several iodoarenes 1,
leading to benzonitriles 2 (Table 2). When a reaction of the
model substrate 1a was performed for 48 h, the yield of 2a was
slightly increased to a 70% isolated yield (Table 2, Entry 1)
compared with that of the reaction for 24 h (64% GC yield,
Entry 8 in Table 1). Sulfur-containing iodoarene 1b was con-
verted into product 2b (Entry 2), and the cyanation of both
alkyl-substituted 1c­1f and unsubstituted iodobenzene 1g
proceeded to form the corresponding benzonitrile derivatives
t
1f, (R = 4- Bu)
d
1g, (R = H)
2g, 69%
I
CN
E
E
c
8
9
1h, (E = CO
1i, (E = Ac)
2
Me)
2h, 47%
2c­2g regardless of the position of the substituent on their
2i, 37%
2j, 47%
2k, 41%
CN
benzene rings (Entries 3­7). Substrates bearing electron-with-
drawing methoxycarbonyl 1h, acetyl 1i, trifluoromethyl 1j, and
cyano 1k groups were also suitable for the reaction and provided
the corresponding products 2h­2k, albeit in slightly decreased
yields (Entries 8­11). With halogen-substituted iodobenzenes
such as 1-fluoro-4-iodobenzene (1l), 1-chloro-4-iodobenzene
10
1j, (E = CF3)
1
1
1k, (E = CN)
I
X
X
(
1m), and 1-bromo-4-iodobenzene (1n), C­CN bond formation
1
1
1
2
3
4
1l, (X = F)
1m, (X = Cl)
2l, 46%
occurred at the carbon­iodine bond selectively over C­F, C­Cl,
and C­Br bonds, giving 4-halo-benzonitriles 2l­2n (Entries 12­
c
2m, 62%
1
4). When 1,4-diiodobenzene (1o) was used as the starting
substrate, a mixture of the mono- and di-cyanation products
o and 2k was obtained in 36 and 23% yields, respectively
Entry 15). Iodoarenes bearing 1-naphthyl, 3-pyridyl, and 2-
c
1n, (X = Br)
2n, 54%
2
(
I
CN
1
1
5
6
I
I
thienyl moieties 1p­1r were also applicable to the cyanation by
nitromethane, and afforded products 2p­2r in 43­78% yields
1o
2o, 36% (2k, 23%)
(Entries 16­18).
The mechanism for cyanation by nitromethane remains
unclear, because nitromethane has never been utilized as a CN
source in copper-catalyzed aromatic C­CN bond formation.
I
CN
7
Two plausible pathways for this reaction are described in
Scheme 2. A mechanism that begins with the conversion of
nitromethane to a cyanide ion is possible (path a), in which a
C­C bond formation process is considered to be similar to a
1p
2p, 78%
I
CN
N
N
1
1
7
8
1
q
2q, 43%
via "CN" generation (path a)
I
CN
S
S
I
I
CN
CN
Ar
+
CH
NO
Ar
+
"CN"
Ar
3
2
1
r
2r, 44%
via nitromethylation (path b)
aReaction conditions: 1 (1 mmol), CuBr (0.2 mmol), DMAP
(1 mmol), and N-methylpiperidine (1 mmol) in CH3NO2 (1 mL,
ca. 18.6 mmol) at 100 °C for 24 h. Isolated yield. 48 h. GC
yield (56% isolated yield of 2g).
I
2 2
CH NO
Ar
+
CH
NO
Ar
Ar
3
2
b
c
d
Scheme 2. Hypothetical reaction pathways.
Chem. Lett. 2017, 46, 1736–1739 | doi:10.1246/cl.170798
© 2017 The Chemical Society of Japan | 1737

picrate paper
yellow
CuBr
DMAP (1 equiv)
Et N (1 equiv)
2
(cat)
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I
CN
3
"
CN"
CH NO
100 °C, 20 h
3
2
MeO
MeO
1a
2a
red
Scheme 3. Detection of HCN by picrate paper test.
previously established coupling between aryl halides with metal
cyanides, as described in Scheme 1A.2 A reaction via the
nitromethylation of aryl iodides by nitromethane is another
possible mechanism (path b).6 In that case, the production of
the cyano group would occur after the C­C bond formation.
­4
2
3
o,11
4
A cyanide anion is a possible intermediate in path a, and
can be detected using a picrate paper test.6
e,6f
This detection
method is based on a principle whereby the reaction between
HCN and either picric acid or picrate ion provides a red-colored
compound. Picrate paper is filter paper moistened with picric
acid and Na2CO3 in water. After the cyanation of 4-methoxy-
iodobenzene (1a) in the presence of CuBr2, DMAP, and Et3N in
nitromethane at 100 °C for 20 h, picrate test paper was changed
to red when exposed to the moisture of the reaction flask, which
indicated the in situ formation of a cyanide anion (Scheme 3).
Path b is another mechanism for which the (nitromethyl)-
benzene derivative is a plausible intermediate. However, when
5
1
2
1
-methyl-4-(nitromethyl)benzene (3) was used as the starting
substrate, and was treated with CuBr2, DMAP, and Et3N in
nitromethane at 100 °C for 20 h, the conversion of (nitro-
methyl)benzene 3 to the corresponding benzonitrile 2e was not
observed (eq 7).
CuBr
DMAP (1 equiv)
Et N (1 equiv)
2
(cat)
CH
2
NO
2
CN
3
(
7)
CH NO
00 °C, 20 h
3
2
1
3
2e
not detected
3
374. m) Q. Wen, J. Jin, Y. Mei, P. Lu, Y. Wang, Eur. J. Org.
It is not obvious which pathway proposed in Scheme 2 is
plausible, but these results imply that the mechanism via “CN”
generation follows C­CN bond formation (path a), which
is more likely than nitromethylation (path b) for the present
cyanation.
In summary, we found that nitromethane can be transformed
into a cyanide equivalent under the Cu/base system, which was
indicated by the picrate paper test. Based on those results, the
application of catalytic cyanation for the synthesis of aryl nitriles
using nitromethane as a CN reagent was achieved. The 18
examples of aromatic iodides could be applied to this conversion
to form the corresponding benzonitrile derivatives in moderate
to good yields. This in situ method generates “CN” species
using simple and easily handled nitromethane, and can be
regarded as a convenient method for C­CN bond formation due
to the avoidance of the typical toxic metal cyanides.
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6
This work was partially supported by JSPS KAKENHI
Grant Number JP16K21400.
Supporting Information is available on http://dx.doi.org/
1
0.1246/cl.170798.
References and Notes
#
They contributed equally.
1
Representative reviews on aromatic C­CN formations:
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© 2017 The Chemical Society of Japan

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12 A cyanide anion was also detected by the picrate paper test
under the following conditions: CuBr2 (20 mol %), DMAP
(1 equiv), and N-methylpiperidine (1 equiv) in nitromethane
(1 mL) at 100 °C for 6 h, without 4-methoxyiodobenzene
(1a).
7
8
9
10 N. Sakai, M. Sasaki, Y. Ogiwara, Chem. Commun. 2015, 51,
Chem. Lett. 2017, 46, 1736–1739 | doi:10.1246/cl.170798
© 2017 The Chemical Society of Japan | 1739