Tetrahedron Letters
Synthesis of aryloxyacetonitriles based on arylboronic acids
with 2-bromoacetonitrile
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Yingmin Li, Mengping Guo , Yongju Wen, Lanjiang Zhou, Xiuli Shen, Yangping Kang
Institute of Coordination Catalysis, College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient protocol for the synthesis of aryloxyacetonitriles based on arylboronic acids with 2-
bromoacetonitrile has been developed using eco-friendly hydrogen peroxide as oxidant under metal-free
conditions. This method is compatible with arylboronic acid attached sensitive substituent and obtains
desired product in moderate to good yield.
Received 14 May 2020
Revised 29 July 2020
Accepted 2 August 2020
Available online 16 August 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Arylboronic acid
Hydrogen peroxide
Green synthesis
Aryloxyacetonitriles
Aryl oxyacetonitriles are important organic compounds as ver-
satile precursors in synthesis of pharmaceuticals [1–4]. The nitrile
pharmacophore plays a significant role in modulating the biologi-
cal activities of synthetic medicinal drugs and natural products
[5–9]. Additionally, the cyano group can be easily converted to
other functional groups, such as carboxyl derivatives, amines,
ketones, and various heterocycles [10–14]. Therefore, the concise,
cost-effective and environmentally friendly methods for assem-
bling aryloxyacetonitriles should be deserved more attention. In
the past few years, the perfluorobutyl iodide-promoted
cyanomethylation of phenols with acetonitrile for the synthesis
of the aryloxyacetonitriles has been reported in the presence of
NaH through a cyanomethyl radical pathway [15] (Scheme 1).
More recently, A metal-free direct C(sp3)–H cyanation reaction
with cyanobenziodoxolones and anisole derivatives for preparing
aryloxyacetonitriles has been developed. In this reaction,
cyanobenziodoxolones are both cyanating reagents and oxidants
[16] (Scheme 2). However, the direct use of inexpensive, commer-
cially available starting material to undergo reaction has attracted
much interest in organic chemistry. Investigation showed that
arylboronic acids, which have the advantages of versatile nature,
structural diversity, low toxicity, easy availability, greater stability
and reactivity, can be easily converted into corresponding phenols
by oxidative hydroxylation [17–22]. Cao’s work showed that
unsymmetrical biaryl ethers were synthesized via a novel Ni-cat-
alyzed cross-coupling reaction of polyfluoroarenes with aryl-
boronic acids and oxygen [23]. Herein, we report the first
example of efficient methods for the synthesis of the aryloxyace-
tonitriles based on arylboronic acids with 2-bromoacetonitrile
without transition metal catalyst using H2O2 as a green oxidant
(Scheme 3).
We started with a model reaction of phenylboric acid 1
(0.5 mmol) with 2-bromoacetonitrile 2 (0.7 mmol), which was con-
ducted in H2O (3 mL) at 80 °C in the presence of H2O2 (0.08 mL),
giving 25% yield of 2-phenoxyacetonitrile 3a (Table 1, entry 1).
Consequently, the reaction conditions by varying the ratio of start-
ing materials, solvents, bases, amounts of oxidant, times and tem-
peratures were examined, and the yield of 3a improved to 74%
using NaOH as base in DMF (Table 1, entry 2). This encouraged
us to explore the effect of bases and, as a result, the yield of 3a
was poor with other bases (Table 1, entry 8–12). Then, the effects
of the ratio of starting materials 1:2 were examined, and relatively
high yield at the proportion of 1:1.4 was chosen as the the ratio of
starting materials 1:2 (Table 1, entry 2, 13–16). Investigating the
effect of the amount of oxidant H2O2 on this reaction clearly
showed that 0.08 mL was the most appropriate amount for the
synthesis of phenyloxyacetonitriles (Table 1, entry 2, 17–19). Fur-
ther optimizations showed that increasing the reaction time did
not improve the yield (Table 1, entries 22) and decreasing or
increasing reaction temperature obtained the lower yields (Table 1,
entries 20–25). Therefore, the reaction conditions of entry 2 proved
to be optimal.
Next, we were interested to demonstrate the general applica-
bility of this method for the synthesis of structurally diverse and
challenging aryloxyacetonitriles. As shown in Table 2, aryl-
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Corresponding author.
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Li, Yingmin
