Copper(II)-mediated formation of oxazole-4-carbonitrile from acetophenone and coordinated cyanide anion: Via a radical coupling

Article abstract of DOI:10.1039/c7ra01983a

A protocol for the direct synthesis of 5-aryloxazole-4-carbonitrile from acetophenone was first described with potassium ferricyanide as a cheap and low toxicity cyanide reagent, in which, multiple bond formation was implemented via an oxygen mediated radical mechanism. Potassium ferricyanide played a dual role as a CN source and also as a coupling partner for the cyclization of oxazole.

Full text of DOI:10.1039/c7ra01983a

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Copper(II)-mediated formation of oxazole-4-
carbonitrile from acetophenone and coordinated
Cite this: RSC Adv., 2017, 7, 24643
cyanide anion via a radical coupling†
Congjun Xu,‡ Mingze Qin,‡ Jun Yi, Yanjing Wang, Yanfeng Chen, Bingfu Zhang,
Yanfang Zhao* and Ping Gong
*
Received 17th February 2017
Accepted 30th April 2017
A protocol for the direct synthesis of 5-aryloxazole-4-carbonitrile from acetophenone was first described
with potassium ferricyanide as a cheap and low toxicity cyanide reagent, in which, multiple bond formation
was implemented via an oxygen mediated radical mechanism. Potassium ferricyanide played a dual role as
a “CN” source and also as a coupling partner for the cyclization of oxazole.
DOI: 10.1039/c7ra01983a
rsc.li/rsc-advances
Oxazole derivatives, one of the most important heterocyclic we found that 5-phenyloxazole-4-carbonitrile was obtained
1
compounds, are widely present in natural products, synthe- smoothly in the absence of Pd(AcO)2.
2
3
sized drugs and advanced materials. Meanwhile, a signicant
To gain a better understanding of this attractive result, we
proportion of drugs used in clinical treatment contain a cyano systematically studied the function of oxidants and cyanide
4
group. In addition, the introduction of a cyano group to small- (Table 1). At the beginning of the investigation, the reaction of
molecule lead compounds is one of the most critical strategies acetophenone (1a), DMF, and potassium ferricyanide was
ꢀ
in drug development because the cyano group can be easily examined in the presence of CuI
2
(1.0 equiv.) at 130 C for 12 h.
converted into amide, carboxylic acid, imido ester, amidine, The expected 5-phenyloxazole-4-carbonitrile (2a) was obtained
5,6
and methyl ammonia groups. Thus, the introduction of in 29% yield with the formation of side product N,N-dimethyl-2-
13
a cyano group to an oxazole ring is an appealing idea.
oxo-2-phenylacetamide in 19% yield, and 40% of raw material
Over the years, many strategies for the preparation of cyano- was recovered (Table 1, entry 1). The reaction did not occur in
oxazoles have been developed, which includes the dehydration the absence of CuI or K [Fe(CN) ] (entries 2 and 3). The other
2
3
6
7
–9
of carboxamides to nitriles,
nucleophilic substitution on oxidants such as CuI, FeBr
3
and ZnBr
2
were investigated (entries
was used as the
10
oxazoles and intramolecular condensation of b-acyloxyen- 4–10). The yield of 2a was up to 75% when CuBr
2
11
amines (Scheme 1). These methods suffered from harsh oxidant (entry 10). It was found out that the effects of Cu(II) salts
reaction conditions, toxic reagents or unavailable starting and Fe(III) salts was superior to Cu(I) salts in the system. Organic
materials. Herein, exploring the potential of non-toxic and oxidants, such as NBS, were tested to enhance the conversion of
efficient systems is imperative, which might provide a smooth this reaction. However, only inferior conversion was observed
approach to construct carbonitrile from ubiquitously present (entries 12). The use of KCN, CuCN or K [Fe(CN) ] instead of
4
6
substrates.
Initially, the authors tried to develop an efficient cyano
K [Fe(CN) ] also led to the formation (entry 15–17), but only
3 6
12
substitution reaction via C–H bond activation with acetophe-
none as the substrate using nontoxic cyanide sources, such as
potassium ferricyanide and potassium ferrocyanide (Scheme 2).
Quite incidentally, 5-phenyloxazole-4-carbonitrile was obtained
dramatically in the presence of CuI and Pd(OAc) with DMF as
2
2
solvent (Scheme 2). The surprising results aroused our inter-
esting and the reaction was investigated further. Subsequently,
Key Laboratory of Structure-based Drug Design and Discovery, Shenyang
Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe
District, Shenyang 110016, People's Republic of China. E-mail: yanfangzhao@126.
com; gongpinggp@126.com
†
1
‡
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra01983a
These authors contributed equally to this work.
Scheme 1 Synthesis of oxazole-4-carbonitrile.
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Scheme 3 Control experiments for investigating the role of DMF.
Scheme 2 A surprising result.
3 6
the “CN” in K [Fe(CN) ] also participated in the cyclization
rather than DMF.
a
Table 1 Optimization of the reaction conditions
With the optimized conditions in hand (Table 1, entry 10),
the scope of substrates for the reaction was explored. The
structures and yields of the products are summarized in
Scheme 4.
Almost all of the starting acetophenones bearing mono-
substitution or poly-substitution were successfully transformed
into the desired 4-carbonitrile products in moderate to good
b
Entry
Oxidant
Cyanide
Yield (%) yields. In addition, the electronic properties of the substituents
on the aromatic ring signicantly inuenced the efficiency of this
transformation. The reactions of 4-uoro, 4-bromo, and 3-chloro
acetophenone proceeded smoothly to afford the corresponding
products (2f–2h) in excellent yields. Furthermore, the optimized
reaction conditions were also applicable to acetophenones with
the electron-donating substituents (2b–2d). However, the strong
2
electron-withdrawing groups on acetophenone, such as –NO ,
1
2
3
4
5
6
7
8
9
CuI
—
2
K
K
—
3
Fe(CN)
Fe(CN)
6
29
NR
NR
NR
Trace
40
NR
50
NR
75
26
Trace
39
70
43
NR
71
3
6
CuI
2
CuCl
CuI
FeBr
ZnBr
CuCl
CuBr
CuBr
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
Fe(CN)
6
6
6
6
6
6
6
6
6
3
2
2
hindered the conversion (2i and 2j) and the reaction required
a high temperature. A low yield was observed in the case of 2-
substituted acetophenones (2j–2l) due to the inuence of steric
hindrance. Besides, the reactions of methyl 4-acetylbenzoate
proceeded smoothly to afford the corresponding products (2e),
10
11
12
15
16
17
18
19
2
CuO/I
NBS
2
CuBr
CuBr
CuBr
CuBr
CuBr
2
CuCN
KCN
2
2
2
2
18a
while, the starting acetophenones bearing aldehydes or acids
were hardly transformed into the desired 4-carbonitrile products.
K
4
K
3
K
3
Fe(CN)
Fe(CN)
Fe(CN)
6
6
6
c
d
a
3 6
Reaction conditions: 1a (1.0 mmol), K [Fe(CN) ] (0.4 mmol) or KCN
(
2.0 mmol) or CuCN (2.0 mmol), DMF (3 mL), oxidant (1.0 mmol), at
ꢀ
30 C. Isolated yield. Nitrogen atmosphere. NR: no desired
d
b
c
1
product was detected. Oxygen balloon.
using KCN showed good result (entry 16). From the safety and
yield point of view, K [Fe(CN) ] was chosen as the cyanide
3 6
source. Interestingly, in an exclusive nitrogen atmosphere, the
transformation was shut down (entry 18), which indicated that
O
2
play a crucial role in the reaction. In addition, when the
reaction was performed under an O atmosphere, the result was
2
the same as that under an air atmosphere (entry 19).
Next, we turned our attention to the effect of solvent on the
reaction. It turned out that 5-phenyloxazole-4-carbonitrile was
not detected when DMF was replaced with other solvents, such
as acetonitrile, dimethyl sulfoxide, N-methyl-2-pyrrolidone or
ethylene glycol, which indicated that the DMF is indispensable
in the reaction. Considering that DMF has the capability to
14
participate in the reaction, a control experiment with DMF-d7
as the solvent was carried out (Scheme 3). 5-Phenyloxazole-4-
carbonitrile-2-d was not detected, which means that DMF
participate in this reaction only as an excellent solvent involving
Scheme 4 Scope of acetophenones. Reaction conditions: 1a (1.0
mmol), K
3
[Fe(CN)
6
] (0.4 mmol), DMF (3 mL), CuBr
2
(1.0 mmol), at
12a,15
a
ꢀ
ꢀ
coordinated cyanide anion.
Meanwhile, it turned out that 130 C. Isolated yield. At 140 C.
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Subsequently, in order to gain insight into the reaction
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mechanism, several control experiments were performed as
shown in Scheme 5. We proposed a plausible reaction pathway
involving the formation of an intermediate, such as 2-bromo-1-
phenylethan-1-one (3ab) and 3-oxo-3-phenylpropanenitrile (3ac)
16
17
via halogenation and nucleophilic reaction. In subsequent
experiments, both 3ab and 3ac transformed to the desired 2a in
a comparative yields, which implied that the transfer undergo
the halogenation and nucleophilic process. Furthermore, ethyl
benzoylacetate could converse to the desired ethyl 5-
phenyloxazole-4-carboxylate in this system (2ac).
In addition, it is noteworthy that the reaction was inhibited
in the presence of radical scavengers, suggesting the possibility
of a radical pathway (Scheme 6).
On the base of experimental results and according to
16–20
previous studies,
a possible reaction mechanism is
proposed and shown in Scheme 7. Firstly, acetophenone
transferred to 3-oxo-3-phenylpropanenitrile (3ac) via halogena-
Scheme 7 Proposed mechanism.
1
4
15
tion and nucleophilic reaction in the presence of CuBr and
2
II
K [Fe(CN) ]. Next, Cu served as a single electron oxidant to
convert the 3ac to the radical species 4. The Cu CN species
then combines with radical species 4 to generate the Cu -
3
6
the corresponding products in moderate to excellent yields. In
addition, the dramatic multiple bond formation provides
a practical one-pot access to various 5-aryloxazole-4-carbonitrile
derivatives from accessible raw materials. In addition,
a reasonable reaction mechanism was proposed.
18
I
18a
I
bonded radical intermediate 5. Immediately, intermediate 5
19
transformed to the radical intermediate 6 via cyclization,
which was oxidized by CuII to form the cationic intermediate
20
7.
Finally, the desired product 2a is obtained from 7 via
elimination reaction.
In conclusion, an efficient, low-toxicity formation of 5-
aryloxazole-4-carbonitrile from acetophenone was developed
using potassium ferricyanide as a cyanide reagent with Cu(II)
bromide as an oxidan, in which, potassium ferricyanide played
a dual role as a “CN” source and also as a coupling partner for
the cyclization of oxazole. The reaction conditions are mild and
suitable for a wide range of substrates. Most of these substrates,
such as 4-uoro, 3-chloro, and 4-bromo acetophenone, provide
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