Copper(I)-mediated cyanation of boronic acids

Article abstract of DOI:10.1002/adsc.201000747

A simple cyanation reaction of boronic acids with cuprous cyanide is achieved, providing nitriles in moderate to good yields. In the presence of copper(I) iodide, trimethylsilyl cyanide is also a good cyanating reagent. The reaction can be conducted on a 10-mmol scale. Thus, this new approach represents an exceedingly practical method for the synthesis of nitriles.

Full text of DOI:10.1002/adsc.201000747

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DOI: 10.1002/adsc.201000747
Copper(I)-Mediated Cyanation of Boronic Acids
a
a
a,
a,
Guoying Zhang, Lingli Zhang, Maolin Hu, * and Jiang Cheng *
a
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325000, Peopleꢀs Republic of China
Fax : (+86)-577-5699-8939; e-mail: jiangcheng@wzu.edu.cn or maolin@wzu.edu.cn
Received: October 2, 2010; Revised: November 25, 2010; Published online: February 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000747.
Abstract: A simple cyanation reaction of boronic
acids with cuprous cyanide is achieved, providing
nitriles in moderate to good yields. In the presence
of copper(I) iodide, trimethylsilyl cyanide is also a
good cyanating reagent. The reaction can be con-
ducted on a 10-mmol scale. Thus, this new approach
represents an exceedingly practical method for the
synthesis of nitriles.
Chang described a palladium-catalyzed cyanation of
CÀH bondsof 2-arylpyridines, using a combined
[10]
source of N,N-dimethylformamide and ammonia.
Nevertheless, the requirement of the chelation group
would limit the substrate scope.
In the past few years, the transition metal-catalyzed
cyanations of aryl halides have been developed as a
useful method for the preparation of aryl ni-
[
11,12,13]
triles.
However, a general problem in these re-
Keywords: boronic acids; copper; cyanation; cyano-
trimethylsilane; nitriles
actions is the high affinity of cyanide towards Pd-,
Cu- and Ni- based catalysts, which often results in a
fast deactivation of the catalytic system. Therefore,
the development of a new cyanation method is of
continuing academic interest.
The boronic acids are particularly attractive syn-
Aryl nitriles are an important class of compounds be- thetic intermediates because of their low toxicity and
[
14]
cause they are not only key components of pharma- easy of handling. Thus, very useful protocols for the
[
1]
ceuticals, natural products, dyes and herbicides, but CÀN, CÀO, CÀS bond-forming processes have been
[
15]
also valuable motifs for the installation of functional previously reported. However, employing the bor-
groups such as aldehydes, amines, amidines, tetra- onic acids as the surrogate in the cyanation reaction
[
2]
zoles, acids and acid derivatives. In addition, nitriles has received little attention. In 2006, Liebeskind re-
are valuable precursors in organic synthesis because ported the palladium-catalyzed and copper(I)-mediat-
they can be easily converted into an array of function- ed coupling of boronic acids and benzyl thiocya-
[
16]
al groups.
nate.
During the preparation of this manuscipt,
[
3]
The Rosenmund–von Braun reaction and Sand- Hartwig reported an iridium-catalyzed borylation of
[4]
meyer reaction are two traditional methods for pre- the arene CÀH bond followed by a copper-mediated
paring aryl nitriles. However, these two methods re- cyanation of the formed arylboronate esters using
[
17]
quired harsh reaction conditions and laborious isola- Zn(CN) to access aryl nitriles. Herein, we report a
2
tion of products. The transition metal-catalyzed func- simple copper(I)-mediated procedure for the cyana-
tionalization of aryl CÀH bonds provides a promising tion of boronic acids with CuCN and TMSCN.
[
5]
alternative to the standard cyanating reactions. In
We initiated our investigation by testing the cyana-
2
009, we reported a palladium-catalyzed direct cyana- tion of 4-methoxyphenylboronic acid with CuCN
tion of CÀH bonds of 2-arylpyridine with CuCN and under air (Table 1). To our delight, the cyanation
a cascade bromination/cyanation reaction of the CÀH product was obtained in 32% yield in DMF (entry 1,
[
6]
bond using K Fe(CN) . Using the same catalytic Table 1). The reaction efficiency was improved by
3
6
system, Reddy developed the palladium-catalyzed cy- adding KHCO as base (entry 2, Table 1). Among the
3
anation of the indole CÀH bond to access 3-cyanoin- bases screened, NaOH and K CO were the best, and
2
3
[
7]
doles.
Subsequently, Daugulis demonstrated the the yields were dramatically increased to 96% by em-
copper-catalyzed cyanation of heterocycle CÀH ploying 3.0 equivalents of base at 608C within 2 h, re-
[8]
bonds. Recently, Wang and co-workers reported the spectively (entries 3 and 5, Table 1). Bases such as
palladium-catalyzed direct cyanation of the indole CÀ NaH, Cs CO and K PO were also effective for this
2
3
3
4
[
9]
H bond with chelation assistance. Very recently, transformation (entries 4, 6 and 7, Table 1). Reactions
Adv. Synth. Catal. 2011, 353, 291 – 294
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
291

Guoying Zhang et al.
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Table 1. Optimization of reaction conditions.
Entry CN sour-
ces
Base
(equiv.)
Solvent
DMF
Yield
[a]
[%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
Zn(CN)2
AgCN
TMSCN
–
32
43
96
89
96
93
43
64
68
<5
KHCO (3) DMF
NaOH (3)
NaH (3)
3
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
THF
K CO (3)
2
3
CsCO (3)
3
K PO (3)
3
4
K CO (3)
2
3
K CO (3)
2
3
0
1
2
3
4
5
6
7
8
K CO (3)
2 3
K CO (3)
ClCH CH Cl <5
2
3
2 2
K CO (3)
H O
<5
2
3
2
[b]
K CO (3)
DMF/H O
23
71
48
2
3
2
K CO (2)
DMF
DMF
DMF
DMF
DMF
2
3
K CO (1)
2
3
[
c]
[d]
K CO (3)
<5 (66)[
<5 (72)[
<5 (91)
2
3
d]
d]
K CO (3)
2
3
K CO (3)
2
3
[a]
Figure 1. Copper(I)-mediated cyanation of boronic acids
[
a]
Reaction conditions: 4-methoxyphenylboronic acid
0.3 mmol, 1.5 equiv.), MCN (0.2 mmol), base, under air,
dry solvent (1 mL), 608C, 2 h.
b]
[a]
with CuCN.
Reaction conditions A: boronic acids
(
(
0.3 mmol, 1.5 equiv.), CuCN (0.2 mmol), K CO (3 equiv.)
2
3
[b]
in dry DMF (1 mL), under air, 608C, 2 h.
NaOH
[
[
[
DMF/H O (1 mL/0.3 mL).
2
(1.5 equiv.) in dry NMP/ClCH CH Cl (1 mL/0.3 mL). Isolat-
2 2
c]
Zn(CN) (0.1 mmol).
2
ed yield.
d]
CuI (0.55 equiv.). Isolated yield.
in other solvents, such as DMSO, NMP, THF, ing to aryl nitriles 2e and 2f, which could be used for
ClCH CH Cl, H O and DMF/H O, provided lower further transfomations. Notably, (E)-styrylboronic
2
2
2
2
yields (entries 8–13, Table 1). Replacing CuCN with acid was also a good reaction partner, and 3-phenyla-
AgCN, Zn(CN) or TMSCN resulted in no reaction. crylonitrile 2l was isolated in 54% yield. Disappoint-
2
However, the cyanation products were isolated in ingly, ortho-substituted arylboronic acids failed to de-
6
0
6%, 72% and 91% yields in the presence of liver the cyanated products, providing homo-coupled
.55 equivalents of CuI, respectively (entries 16–18, (biaryl) or proto-deboylation (arene) by-products.
Table 1). Importantly, this transformation is very prac-
Next, other cyanide sources such as TMSCN,
tical, as it does not require the use of expensive cata- AgCN and Zn(CN) were examined in our procedure
2
lyst, long reaction time, high temperature and the rig- (Table 2). However, only with the dosage of CuI as
orous exclusion of air.
more than 0.55 equivalents did the reaction run
With the optimized conditions A in hand, the scope smoothly under the conditions B. Once again, both
and limitation of the cyanation reaction of boronic electron-deficient and electron-rich arylboronic acid
acids with CuCN were studied, as shown in Figure 1. worked well under the procedure, producing the aryl
As expected, various functional groups, including nitriles in good yields. The strong electron-withdraw-
methoxy, phenyl, chloro, vinyl, formyl, acetyl, carbo- ing nitro group again decreased the reaction’s effi-
methoxy, phenolic hydroxy, methylthio and nitro, ciency but fortunately, the yield was increased to 67%
were well tolerated. Both electron-deficient and elec- by employing K PO as the base in NMP (entry 15,
3
4
tron-rich arylboronic acids worked well under the Table 2). Replacing TMSCN with AgCN and
procedure, producing the aryl nitriles in good yields. Zn(CN) , the corresponding cyanation products were
2
However, the strong electron-withdrawing nitro group isolated in moderate yields, respectively (entries 1, 3
decreased the reaction’s efficiency, and 2n was isolat- and 9, Table 2).
ed in moderate yield. Fortunately, the yield increased
To broaden the scope of the substrates, we carried
to 68% by employing 1.5 equivalents of NaOH in out reactions of arylboroxine 1o and 4-methoxyphe-
NMP/ClCH CH Cl. Particularly, chloro and vinyl nylboronic acid pinacol ester 1p with CuCN and
2
2
groups survived well in the standard procedure, lead- TMSCN under the standard conditions A and B as
292
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 291 – 294

Copper(I)-Mediated Cyanation of Boronic Acids
Table 2. Copper(I)-mediated cyanation of boronic acids with
TMSCN.
Scheme 1. Copper(I)-mediated cyanation of boroxine and
[a]
[b]
boronic acid ester. Reaction conditions A. Reaction con-
ditions B.
Experimental Section
Typical Experimental Procedure for Copper(I)-
Mediated Cyanation of Boronic Acids with CuCN
Caution: Work with cyanides is hazardous; the experiments
and work-up need to be carried out in a well-ventilated fume-
hood.
Under air atmosphere,
a mixture of boronic acids
(
(
0.3 mmol, 1.5 equiv.), CuCN (17.9 mg, 0.2 mmol), K CO3
82.7 mg, 3 equiv.) and dry DMF (1 mL) was stirred in a
2
sealed reaction tube at 608C for two hours. After the reac-
tion was finished, the solvent was evaporated under reduced
pressure and the residue was purified by flash column chro-
matography (petroleum ether/ethyl acetate) on silica gel to
give the product.
[11g]
1
4
-Methoxybenzonitrile
(2c):
H NMR
(CDCl3,
5
2
1
00 MHz): d=7.58 (d, J=9.0 Hz, 2H), 6.95 (d, J=8.9 Hz,
1
3
H), 3.86 (s, 3H); C NMR (CDCl , 125 MHz): d=162.8,
3
34.0, 119.2, 114.7, 104.0, 55.5.
[
a]
Acknowledgements
Reaction conditions B: boronic acids (0.25 mmol,
.25 equiv.), TMSCN (0.2 mmol), CuI (0.55 equiv.),
1
We thank the National Natural Science Foundation of China
K CO (3 equiv.) in dry DMF (1 mL), under air, 608C,
2
3
(
Nos. 20972115 and 21071111), and the Key Project of Chi-
2
h.
[
[
[
b]
c]
d]
nese Ministry of Education (No. 209054) for financial sup-
port.
Zn(CN) (0.1 mmol).
2
AgCN (0.2 mmol).
K PO (3 equiv.), NMP (1 mL). Isolated yield.
3
4
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