Cu2O-mediated room temperature cyanation of aryl boronic acids/esters and TMSCN

Article abstract of DOI:10.1002/cjoc.201200711

A method for the efficient and reliable synthesis of aryl nitriles via the Cu₂O-catalyed cross-coupling of aryl boronic acids or esters and TMSCN is presented. A broad range of substrates decorated by electron-rich and deficient, sterically very congested, and labile functionalities were tolerated. Moreover, the reaction can proceed under mild conditions at room temperature. These advantages paired with the use of cheap, readily available, and halogen-free Cu₂O as catalysts make the protocol an appealing option for aryl cyanations. A method for the efficient and reliable synthesis of aryl nitriles via the Cu₂O-catalyed cross-coupling of aryl boronic acids or esters and TMSCN is presented. The room temperature operation paired with the use of cheap, readily available, and halogen-free Cu₂O as catalysts makes the protocol an appealing option for aryl cyanations. Copyright

Full text of DOI:10.1002/cjoc.201200711

COMMUNICATION
DOI: 10.1002/cjoc.201200711
Cu O-Mediated Room Temperature Cyanation of Aryl Boronic
2
†
Acids/Esters and TMSCN
a,b
b
a,c
,a,b
Yong Ye, Yanhua Wang, Pengtang Liu, and Fushe Han*
a
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street,
Changchun, Jilin 130022, China
b
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning 116024, China
c
Changchun University of Science and Technology, Changchun, Jilin 130022, China
2
A method for the efficient and reliable synthesis of aryl nitriles via the Cu O-catalyed cross-coupling of aryl
boronic acids or esters and TMSCN is presented. A broad range of substrates decorated by electron-rich and defi-
cient, sterically very congested, and labile functionalities were tolerated. Moreover, the reaction can proceed under
mild conditions at room temperature. These advantages paired with the use of cheap, readily available, and halo-
gen-free Cu O as catalysts make the protocol an appealing option for aryl cyanations.
2
Keywords copper, boronic acid, boronic ester, cyanation, aryl nitrile
[
10]
Introduction
zylthiocyanate. Hartwig disclosed a one-pot protocol
via the Ir-catalyzed direct C－H borylation followed by
Cu-mediated cyanation of arylboronates with
Aryl nitriles are valuable structural motifs in a broad
range of areas such as herbicides, agrochemicals, phar-
maceuticals, dyes, and natural products. Moreover, the
nitrile group serves as a versatile group that can be eas-
ily transformed into a diverse class of reactive function-
alities such as carboxylic acids, amides, amines, alde-
[11]
Zn(CN)
2
.
Chang achieved the cyanation of boronic
acids/esters as well as arenes with a combination use of
NH I and DMF as cyanide source promoted by
Cu(NO
4
[12]
3
)
2
.
However, these methods required the use
of a large excess of copper (1.5－3.0 equiv.) and high
temperature, in addition to the use of noble metals as
[1]
hydes, esters, N-containing heterocycles, and so forth.
[
10,11]
While conventional methods for accessing aryl nitriles
were relied mainly on the Rosenmund-von Braun reac-
catalysts in many cases.
Very recently, Beller
boronic acids and N-cyano-N-phenyl-p-methylbenzene
sulfonamide with a single component of Rh-based cata-
lyst. Cheng achieved the cyanation of boronic acids/
[
13]
presented a cyanation of
[2]
[3]
tion and Sandmeyer reaction, much recent efforts
have been focused on the transition-metal-catalyzed
cross-couplings although some novel metal-free proto-
[4]
[5]
[6]
cols were also disclosed. So far, the Pd-, Cu-, and
esters and TMSCN using a substoichiometric amount of
[7]
[14]
Ni-catalyzed cyanation of aryl (pseudo)halides with
various nitrile sources, e.g., NaCN, KCN, Zn(CN)2,
K [Fe(CN) ], CuCN, and TMSCN, etc. has been fre-
Although cheap Cu catalyst was used therein,
CuI.
the procedure generates a substantial amount of I-con-
taining byproducts due to a relatively high catalyst
loading of up to 55 mol%. In addition, the reactions
were performed at an elevated temperature. Thus, the
development of a more efficient and practical method
for the synthesis of aryl nitriles is still highly desirable.
Based on our long-standing experiences on Cu-cata-
4
6
quently reported. In addition, the direct C－H cyanation
has also been investigated although the substrate scope
of this protocol was somewhat limited due to the re-
[
8]
quirement of a chelation group.
Alternatively, the electrophilic cyanation of organo-
metallics represents an attractive pathway for accessing
lyzed C－N bonding formation from boronic acids/
[9]
[15]
aryl nitriles. In this aspect, boronic acids/esters have
received much attention due to their stable, readily
available, and low toxic nature. Moreover, the boron-
containing byproducts can be easily separated from the
products. Thus, Liebeskind reported the Pd-catalyzed
and Cu-mediated cyanation of boronic acids with ben-
esters,
herein, we present that the readily available
O is an efficient catalyst that al-
and halogen-free Cu
2
lows for a very simple and mild cyanation of both bo-
ronic acids and esters with TMSCN. Moreover, the re-
action can be carried out efficiently at room temperature
under the oxygen atmosphere.
*
E-mail: fshan@ciac.jl.cn; Tel.: 0086-431-85262936
Received July 11, 2012; accepted August 26, 2012; published online December 11, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200711 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 27—30
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
27

Ye et al.
COMMUNICATION
Experimental
a
Table 1 Optimization of ligands
General procedure for cyanation of aryl boronic ac-
ids/esters with TMSCN
Cu2O (40 mol %),
L, Et3N (3.0 equiv.)
MeO
B(OH)2 + TMSCN
MeO
CN
MeCN, r.t., 18 h
To an oven-dried Schlenck tube was charged aryl-
boronic acids/esters (1.5 mmol, 2.0 equiv.), N,N'-di-
2
1
a
3a
2
methylenediamine (0.9 mmol, 1.2 equiv.), Cu O (0.3
mmol, 40 mol%), and a magnetic bar. The tube was
evacuated three times under vacuum and backfilled with
N
H
L3
CO2H
N
N
N
N
L1
L2
O
2
, and then connected to an oxygen balloon via a nee-
Me
N
N
Me
Me N
N
H
Me
CO2H
dle. Dried CH CN (3 mL) and TMSCN (0.75 mmol, 1.0
3
N
H
Me
Me
H
equiv.) were injected via syringe. The mixture was
stirred at 25 ℃ for 12 h. The resultant mixture was
evaporated under reduced pressure and the residue was
purified by flash column chromatography on a silica gel
using the mixture of PE and EtOAc as eluents to give
the product. Detailed experimental procedures, H NMR
and C NMR data, and copies of H NMR and
NMR spectra were provided in supporting information.
L4
L6
L5
b
Entry Ligand
equiv. of ligand
Yield /%
1
2
3
4
5
6
7
8
－
－
0
c
L1
L2
L3
L4
L5
L6
L6
L6
1.2
1.2
1.2
1.2
1.2
1.2
0.8
0.4
Trace
1
Trace
Trace
Trace
45
1
3
1
13
C
Results and Discussion
90
Since a general concern in transition-metal-catalyzed
cyanation is the rapid deactivation of the catalysts ow-
ing to the high affinity of cyanide to metal ions, our ini-
tial efforts in the study were focused on the search of an
appropriate ligand which, upon coordination with the
metal ions, is assumed to lower the electrophilicity of
the metal ions toward cyanide. Thus, a range of N-con-
taining ligands was evaluated via the cyanation of
21
9
a
Trace
Reaction conditions: 4-methoxyphenyl boronic acid 1a (1.5
mmol, 2.0 equiv.), TMSCN 2 (0.75 mmol, 1.0 equiv.), Et N (3.0
equiv.), Cu O (40 mol%), and ligand in MeCN (3 mL) at r.t. for
8 h under air. Isolated yield. Monitored by TLC.
3
2
b
c
1
a
Table 2 Optimization of other reaction parameters
4
-methoxyphenyl boronic acid (1a) and TMSCN (2) as
a model reaction (Table 1). Cu O was chosen initially as
the catalyst due to its read availability and halogen-free
nature. The reaction was performed in the presence of
2
Catalyst
(mol%)
1a
b
Run
Solvent Atmos. t/h Yield of 3a
(equiv.)
1
2
3
4
5
6
7
8
9
Cu O (40)
2
2.0
2.0
1.5
2.0
2.0
MeCN air
MeCN air
MeCN air
MeCN air
MeCN air
MeCN air
MeCN air
Toluene air
CH Cl air
18 90%
18 75%
18 50%
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 N.R.
18 38%
18 66%
5.5 95%
3
Et N as base in MeCN at room temperature under air
2
Cu O (35)
atmosphere. Some representative results were summa-
rized in Table 1. Initial trials showed that either in the
absence or in the presence of ligands L1－L4, the reac-
tion was not occurred (Entries 1－5). In contrast, the
cyanated product 3a could be obtained in 45% yield
when the more electron-rich TMEDA (L5) was used
Cu O (40)
2
c
CuCl (40)
CuO (40)
CuSO
(40) 2.0
4
CuCl (40) 2.0
2
(
Entry 6). Encouraged by this result, the efficiency of
Cu
2
O (40)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
some analogues of L5 was further examined. Delight-
edly, we eventually found that the reaction could pro-
ceed very smoothly in the presence of DMEDA (L6),
affording 3a in 90% yield (Entry 7). Attempts toward
further lowering the equivalent of ligand resulted in a
markedly decreased yield of the product (Entries 8 and
Cu O (40)
2
2
2
1
0
1
Cu O (40)
THF
air
air
2
1
Cu O (40)
DMF
2
12 Cu
O (40)
DMSO air
MeOH air
2
13 Cu O (40)
2
9
). These results clearly demonstrated our initial as-
1
1
1
4
5
6
7
Cu
2
O (40)
MeCN
N
2
sumption, that is, the nature of the ligand plays a crucial
role in promoting the cyanation reaction under mild
conditions.
With an appropriate ligand available, we then opti-
mized other parameters such as the types of copper salts
and solvents, the molar ratio of reactants, and the effects
of the reaction atmosphere. As listed in Table 2, among
Cu O (40)
MeCN O2
MeCN O2
MeCN air
2
d
Cu O (40)
12 90%
18 80%
2
d
1
Cu O (40)
2
a
Unless otherwise noted, the reaction conditions were: TMSCN
(0.75 mmol, 1.0 equiv.), 4-methoxyphenyl boronic acid 1a,
DMEDA (L6, 1.2 equiv.), and Et N (3.0 equiv.) in solvent (3 mL)
at r.t. Isolated yield. N.R. stands for no reaction. Et
absent.
3
(
I)
(II)
b
c
d
several Cu and Cu salts, only Cu
complete conversion as well as excellent isolated yield
2
O gave rise to a
3
N was
28
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 27—30

2
Cu O-Mediated Room Temperature Cyanation of Aryl Boronic Acids/Esters and TMSCN
in the presence of ca. 40 mol% catalyst and 2.0 equiv.
of boronic acid (Entries 1－3). In stark contrast, other
copper salts were almost inactive (Entries 4－7). A
screening of a range of solvents showed that MeCN was
the best option (Entry 1 vs. Entries 8－13). In addition,
the effect of reaction atmosphere was inspected. While
under these conditions. Moreover, identical yield (90%)
was also obtained when the reaction was scaled up to
gram scales, suggesting that the method is practical for
large scale synthesis.
Having established the optimized conditions, we
then examined the substrate scope and limitations by
varying the structure of boronic acids (Table 3). Boronic
acids decorated by strong donating groups such as
ethers and thioethers afforded the cyanated products in
high to excellent yields (3a－3e). More to the point, the
sterically congested 2- or 2,6-OMe substituted sub-
strates could also be converted to the aryl nitriles in
good yields (3f and 3g). In addition, smooth reactions
were also observed for the substrates modified by sim-
ple substituents such as Me, t-Bu, and Ph groups (3h－
3j) although the yields were moderated when these sub-
stituents were located at the ortho-position (3k and 3l).
Furthermore, the cyanation efficiency of a range of bo-
ronic acids whose structures were modified by various
electron-withdrawing functional groups was demon-
2
replacement of air with N decreased the yield of 3a
from 90% to 66% as a comparison of Entry 1 vs. 14
shows, a much more rapid conversion paired with a
slightly increased yield was observed when the reaction
was performed under an oxygen atmosphere (Entry 1 vs.
1
5). More delightedly, we found that, under the oxygen
atmosphere, the cyanation occurred also very efficiently
even in the absence of Et N (Entries 16 vs. 17). This
3
makes the reaction can be performed under an environ-
mentally more benign condition. Thus, the optimized
conditions for the cyanation of boronic acids 1a and
TMSCN are: Cu O (40 mol%) and DMEDA (L6, 1.2
2
equiv.) in MeCN at room temperature for 12 h under an
oxygen atmosphere. 3a could be obtained in 90% yield
a
2
Table 3 Cu O-catalyzed cyanation of various boronic acids and boronic esters
a
Reaction conditions: Aryl boronic acid 1 (1.5 mmol, 2.0 equiv.), TMSCN (0.75 mmol, 1.0 equiv.), DMEDA (L6, 1.2 equiv.), O
2
(in balloon), and Cu
2
O
b
(
40 mol %) in MeCN (3 mL) at r.t. for 12 h; average isolated yield of two to three runs. The reaction was run for 30 h at r.t.
Chin. J. Chem. 2013, 31, 27—30
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
29

Ye et al.
COMMUNICATION
strated. The results showed that ketone (3m), ester (3n),
nitro (3o and 3p), and halogen (3q and 3r) groups were
well-tolerated under the reaction conditions. Finally, a
fused aromatic substrate could also be cyanated in ex-
cellent yield (3s). It should be mentioned that the reac-
tion of the 2-heterocyclic boronic acids was inefficient
with deboronated byproducts being detected. Indeed, the
instability of 2-heterocyclic boronic acids (3t and 3u)
makes them a considerable challenge in other transi-
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Conclusions
In summary, we have developed a practical and re-
liable method for the cyanation of both aryl boronic ac-
ids and esters with TMSCN by using Cu O as catalyst.
Notable features of this approach are: (1) the readily
available, stable, and less toxic boronic acids/ester and
TMSCN are used as substrates. (2) The cheap and
2
halogen-free Cu O is used as catalyst. (3) The reaction
2
2
1
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proceeds smoothly at room temperature. (4) Most im-
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can be easily scaled up to gram scales. Owing to these
advantages, the method presented herein represents one
of the most efficient ones for practical and reliable syn-
thesis of aryl nitriles. Finally, based on the ligand strat-
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2
[
[
[
[
5
Acknowledgement
2
Financial support from Hundred Talent Program of
CAS and State Key Laboratory of Fine Chemicals (No.
KF1008) is acknowledged.
(Lu, Y.)
30
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 27—30