Novel α-arylnitriles synthesis via Ni-catalyzed cross-coupling of α-bromonitriles with arylboronic acids under mild conditions

Article abstract of DOI:10.1039/c1ob05326d

An applicable and easy-handling Ni-catalyst can be used to promote direct arylation of α-bromonitriles with various arylboronic acids to construct α-arylnitriles under mild conditions. The methodology tolerates β-hydrogens and functional groups in the substrates.

Full text of DOI:10.1039/c1ob05326d

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Novel a-arylnitriles synthesis via Ni-catalyzed cross-coupling of
a-bromonitriles with arylboronic acids under mild conditions†
Yingying Yang,a Shan Tang,a Chao Liu,a Huimin Zhang,a Zhexun Suna and Aiwen Lei*a,b
Received 1st March 2011, Accepted 12th May 2011
DOI: 10.1039/c1ob05326d
An applicable and easy-handling Ni-catalyst can be used
to promote direct arylation of a-bromonitriles with various
arylboronic acids to construct a-arylnitriles under mild condi-
tions. The methodology tolerates b-hydrogens and functional
groups in the substrates.
(Fig. 1, Path II),13 in which aryl groups are used as nucleophiles,
such as aryl triflorosilanes, aryl boronic acids and aryl zinc
reagents. From the nature of these two approaches, the advantages
of the second one are very obvious. The reaction conditions
are milder. Strong bases are avoided in the deprotonation of
the nitriles, hence the functional groups tolerance is highly
improved. However, very few results have been reported by this
protocol. In 2007, aryl triflorosilanes were reported to couple with
a-halonitriles,14 and arylboronic acids were employed in the
a-arylation of a-halocarbonyl compounds.15
To explore new entries toward the synthesis of a-arylnitrles,
we envisioned that arylboronic acids would be proper choices to
react with a-halocarbonyl compounds in the presence of transition
metal catalysts (Fig. 1, Path II). As the Suzuki coupling normally
leads to a mild method for such transformation, and have better
functional groups tolerance.16–20 Herein, we communicate our
recent efforts for the a-arylation of nitrles.
Ni(PPh3)4 was firstly applied as the catalyst to achieve the
coupling between arylboronic acids and a-bromonitriles in the
presence of K3PO4 in toluene. Surprisingly, it worked very
well with not only simple a-bromoacetonitrile, but also the a-
bromobutanenitrile 2b and a-bromopentanenitrile 2c bearing b-
hydrogens (Table 1). Various arylboronic acids could be intro-
duced. The bulky o-tolylboronic acid proceeded well to afford the
desired product. Aryl bromides were also well tolerated, indicating
the potential for further functionalization.
The a-aryl substituted nitrile moieties are very important con-
stituents in many medicinal and natural products.1 With their
impressive bioactivities, they are extensively used as synthetic
intermediates in the pharmaceutical industry.2–4 For example,
Ariflo (Cilomilast) has been used in the clinic for bronchial
asthma and chronic obstructive pulmonary disease (COPD).5–6
However, only limited methods for the synthesis of a-aryl nitriles
have been reported until recently. An early result was reported
in 1996, in which the electrochemical reduction of 1-bromo-3-
(trifluoromethyl)benzene with 2-chloropropanenitrile led to the
cross-coupled product in 62% yield in the presence of nickel
catalyst.7 Later on, Pd-catalyzed protocols were demonstrated
with aryl halides and nitriles in the presence of a strong base.8–12
A
milder process for the synthesis of a-aryl nitrile compounds was
recently reported in which a-silyl nitriles and zinc cyanoalkyls were
directly coupled with aryl halides in the presence of a palladium
catalyst.6 In these cases, the aryl group all acted as an electrophile
(Fig. 1, Path I). Normally, a strong base has to be employed for the
deprotonation of nitriles to form the active nucleophiles, resulting
in the limitation of the functional groups tolerance.
Ni(PPh3)4 is not air-stable and normally requires inert atmo-
sphere operations such as glove box techniques, which limits the
application of this protocol. On the other hand, Ni(PPh3)4 is
usually prepared by the reduction of the mixture of Ni(acac)2
and PPh3 with DIBAL-H.21 To improve the operability of this
transformation, we tried to use the air-stable Ni(acac)2 and
PPh3 directly as catalyst precursor to achieve this cross-coupling
process. Fortunately, it works as well as the Ni(PPh3)4. This result
encouraged us to further optimize the catalyst system.
Fig. 1 Two possible approaches to obtain a-aryl nitriles.
However, from the disconnection of the designed products
a-aryl nitriles, an alternative approach also has high potentials
First, we tried to optimize the ratio of the Ni(acac)2 and PPh3.
a-Bromovaleronitrile and phenylboronic acid were used in the
model reactions. The reactions were analyzed by GC in a span of
25 h (Fig. 2, and see ESI†). The results showed that when the ratio
of Ni(acac)2 and PPh3 is 1 : 2, it gave the highest yield (92%) and
finished in the shortest time (1 h).
This finding promoted us to apply this new catalyst system to the
above-mentioned arylation of a-bromonitriles. Fortunately, most
of the substrates worked well with high yields in the presence of 5%
aCollege of Chemistry and Molecular Sciences, Wuhan University,
P. R. China. E-mail: Aiwenlei@whu.edu.cn; Fax: (+86)-27-68754067;
Tel: (+86)-27-68754672
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, 730000,
Lanzhou
† Electronic Supplementary Information (ESI) available. See DOI:
10.1039/c1ob05326d
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Table 1 Arylation of a-bromonitriles with ArB(OH)2 by using Ni(PPh3)4
Table 2 Arylation of a-bromonitriles with ArB(OH)2 by using Ni(acac)2
as the catalyst precursora
and PPh3 as the catalyst precursora
Entry ArB(OH)2
1
a-Bromonitrile Product
Yield [%]b
67c
Yield
Entry ArB(OH)2
1
a-Bromonitrile Product
[%]b
68c
2
3
4
5
6
76
75
81
78
86
2
3
4
5
81
88
89
75
2b
2b
2b
2c
2c
2c
6
2c
86
a Conditions: See ESI.† b Isolated yield. c GC yield.
a Conditions: See ESI.† b Isolated yield. c GC yield.
Since arylboronic acid esters can be easily prepared by direct
borylation of arenes, they have been increasingly used in coupling
reactions.22 A sample arylboronic ester was appiled to this
arylation reaction to couple with the a-bromonitriles (Table 3).
The catalyst system gave us very positive results. Even though it is
a hindered arylboronic ester, it can couple with the nitriles bearing
b-hydrogens (Entry 2 and 3, Table 3) in high yields (95% and 87%).
In conclusion, we reported the Ni-catalyzed a-arylation of
nitriles by using readily prepared a-bromonitriles and arylboronic
acids or esters which are being widely used in synthetic chemistry
for the first time. The use of Ni(acac)2 and PPh3 as the catalyst
precursor has a significant practical advantage over the reported
methods.
Fig. 2 Arylation of a-bromovaleronitrile with phenylboronic with differ-
ent ratios of Ni(acac)2 and PPh3 (x = 0, 5, 10, 15, 20).
Acknowledgements
of Ni(acac)2 and 10% of PPh3 as catalyst and K3PO4 as additive
(Table 2). Moreover, naphthalen-2-ylboronic acid and naphthalen-
1-ylboronic acid also gave good results (Entry 5 and Entry 6 in
Table 2).
This work was supported by the National Natural Science Founda-
tion of China (21025206, 20832003, 20972118 and 20772093) and
the “973” Project from the MOST of China (2011CB808600). We
also thank the support from “the Fundamental Research Funds
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Table 3 Arylation of a-bromonitriles with ethyl 2-(5,5-dimethyl-1,3,2-
dioxaborinan-2-yl)benzoate by using Ni(acac)2 and PPh3 as the catalyst
precursora
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The Royal Society of Chemistry 2011
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