Copper-catalyzed direct cyanation of terminal alkynes with benzoyl cyanide

Article abstract of DOI:10.1016/j.tetlet.2018.11.049

Copper-catalyzed direct cyanation of terminal alkynes is achieved using less toxic, stable and easy to handle benzoyl cyanide as a cyanide source and air as an oxidant. This protocol provides a good alternative to the preparation of 3-arylpropiolonitriles

Full text of DOI:10.1016/j.tetlet.2018.11.049

Accepted Manuscript
Copper-catalyzed direct cyanation of terminal alkynes with benzoyl cyanide
Yan Du, Zheng Li
PII:
S0040-4039(18)31386-8
https://doi.org/10.1016/j.tetlet.2018.11.049
TETL 50434
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
30 September 2018
13 November 2018
19 November 2018
Please cite this article as: Du, Y., Li, Z., Copper-catalyzed direct cyanation of terminal alkynes with benzoyl cyanide,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.049
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Graphical Abstract
Copper-catalyzed direct cyanation of
terminal alkynes with benzoyl cyanide
Leave this area blank for abstract info.
Yan Du, Zheng Li*
O
Cu(NO3)2
3H2O
Air, DMF, 50 oC, 6 h
CN
H
+
CN
R
R
Air as an oxidant
Mild condition
Less toxic cyanating agent

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-catalyzed direct cyanation of terminal alkynes with benzoyl cyanide
Yan Du, Zheng Li*
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper-catalyzed direct cyanation of terminal alkynes is achieved using less toxic, stable and
easy to handle benzoyl cyanide as a cyanide source and air as an oxidant. This protocol provides
a good alternative to the preparation of 3-arylpropiolonitriles under mild condition.
2018 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Terminal alkyne
Benzoyl cyanide
Cyanation
Propiolonitrile
Introduction
isocyanoiminotriphenylphosphorane [10] (Scheme 1). However
some methods use strongly toxic cyanating reagents, excess
Propiolonitriles are core structural motifs in biologically
active molecules. For example, APN-TMPP can be used as a
peptide probe [1] and CBTF as a precursor of antibody drug [2]
(Fig. 1). Propiolonitriles are also versatile synthons in organic
chemistry for the synthesis of various heterocyclic compounds
associated with interesting chemical and biological properties [3].
In addition, the important two functionalities of propiolonitriles,
alkyne and nitrile, can be served as a versatile building block and
easily transformed into various derivatives, such as amides,
amidines, amines, and triazoles etc [4]. Although the synthesis of
propiolonitriles can start from many substrates [3, 5], the typical
methods generally utilize the reactions of terminal alkynes with
cyanating agents, which include i) the direct cross coupling
between terminal alkynes and CuCN or NaCN [6]; ii) the copper-
catalyzed reactions of terminal alkynes with cyanogen iodide [7];
iii) the copper-catalyzed direct cyanation of terminal alkynes
using AIBN (azobisisobutyronitrile) as a cyanide source [8]; iv)
the electrophilic cyanation of terminal alkynes using 1-
catalysts and harsh reaction conditions. Therefore it is of great
importance to explore a mild, safe and simple way to synthesize
propiolonitriles.
Benzoyl cyanide is a stable and less toxic chemical. It can be
easily prepared by the reaction of nontoxic and inexpensive
K4[Fe(CN)6] with benzoyl chloride according to our investigation
[11]. It has been also used for the cyanide source in organic
synthesis [12]. Herein, we report an efficient method for copper-
catalyzed direct cyanation of terminal alkynes with benzoyl
cyanide under mild condition using air as an oxidant.
Previous work
FeCl3, MeOH
R
CN
R
H
CuCN
ICN
+
N
[Cu],
H
R
CN
R
H
+
CN
[Cu], 80 oC, 12 h
N
O
R
R
H
H
R
CN
+
O
N
O
O
NC
N
n-BuLi, THF, -78 o
C
O
O
F
F
F
F
R
CN
N
+
+
P
O
N
NaO3S
O
O
CN
CN
[Ag], H2O, 80 oC, 6 h
DMF
O
O
R
Ph3P
N
NC
R
CN
H
O
NH
This work
R
NC
APN-TMPP (peptide probe)
CBTF (precursor of antibody drug)
O
Cu(NO3)2
3H2O
+
CN
H
R
CN
Air, DMF, 50 oC, 6 h
Fig. 1 Representative examples bearing 3-arylpropiolonitrile
Scheme 1 Preparation of propiolonitriles
cyanobenzotriazole [9]; and v) the silver-catalyzed direct
cyanation
of
terminal
alkynes
with
N-
 Corresponding author. e-mail: lizheng@nwnu.edu.cn

2
Tetrahedron Letters
d
e
Results and Discussion
Under N2 atmosphere. 0.05 mmol of catalyst was used. 0.1 mmol of
catalyst was used. f 0.5 mmol of catalyst was used.
Initially the reaction of phenylethyne with benzoyl cyanide
was selected as the model reaction to screen the optimal
conditions. The different catalysts and solvents at different
temperature were investigated. The results are summarized in
By using the optimized conditions, synthesis of 3-
arylpropiolonitriles were examined by reactions of terminal
alkynes with benzoyl cyanide in DMF under open air condition
o
Table 1. The reaction was first tested in DMF at 50 C in the
absence of a catalyst, but no product was detected (Table 1, entry
1). The Cu(I) salts such as CuI and CuBr as catalysts were
investigated (Table 1, entries 2, 3). To our delight, 3-
phenylpropiolonitrile (2a) could be obtained in good yield when
using
Cu(NO3)2·3H2O
as
a
catalyst.
The results were summarized in Table 2. It was found that 3-
arylethynes containing electron-donating groups, such as 4-
substituted Me, n-Pr, n-Bu, t-Bu, Amyl and MeO, on aromatic
rings afforded the corresponding products in good yield (2a-2g).
In contrast, 3-arylethynes bearing electron-withdrawing groups
(F, Cl, Br, NO2 and CHO) on their aromatic rings afforded the
desired products in high yield (2h-2m). These results indicated
that electron effect has a certain impact on the yield. Electron-
withdrawing effect can increase the nucleophilicity of terminal
carbon of alkynes and benefit the attack of CN- in the reaction. In
addition, aliphatic terminal alkynes, such as 1-heptyne and
cyclopropylethyne, were also tested for the cyanation with
benzoyl cyanide. Unfortunately no any products were observed.
o
the reaction was catalyzed by CuI in DMF at 50 C for 6 h in
open air (Table 1, entry 2). The Cu(II) salts such as Cu(OAc)2,
CuSO4, CuCl2 and Cu(NO3)2·3H2O as catalysts exhibited
different effects for the reaction (Table 1, entries 4−7). The best
yield (79%) was obtained by using Cu(NO3)2·3H2O as a catalyst
(Table 1, entry 7). Furthermore, the higher temperatures were
also tested, but the reaction yield could not be further improved
(Table 1, entries 8, 9). In addition, the other organic solvents
were also attempted for the reaction. However, low yield of 2a
was isolated in DMSO and MeCN (Table 1, entries 10, 11), and
no product was obtained in MeOH, dioxane, THF and PhMe. The
reaction was also tested under nitrogen atmosphere, but no
product 2a was observed (Table 1, entry 12). This result implied
that air is an indispensable condition for the reaction.
Table 2. Synthesis of 3-arylpropiolonitrilesa
O
Cu(NO3)2
3H2O
CN
Table 1 Optimization of the reaction conditionsa
H
CN
+
Air, DMF, 50 oC, 6 h
R
R
O
Catalyst
CN
CN
H
+
CN
CN
CN
Solvent
2a
1a
2a
2b
79%
70%
2c
67%
Entry
Catalyst
Solvent
Temperature
Yield
(oC)
(%)b
1
None
DMF
DMF
DMF
DMF
DMF
DMF
50
0
CN
CN
CN
2
CuI
50
50
50
50
50
50
80
120
50
50
50
50
50
50
64
2f
66%
2e
%
65
2d
69%
3
CuBr
Trace
Trace
32
4
Cu(OAc)2
CuSO4
CuCl2
O
CN
F
CN
Cl
CN
5
2g
2h
83%
53%
2i
85%
6
43
O2N
CN
CN
Br
CN
7
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMSO
Cu(NO3)2·3H2O MeCN
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMF
Cu(NO3)2·3H2O DMF
79
Cl
2j
2k
80%
62%
2l
84%
8
62
9
48
OHC
CN
2m
77%
10
11
12 c
13d
14 e
15 f
53
aReaction conditions: arylethyne (1 mmol), benzoyl cyanide (1 mmol),
25
o
Cu(NO3)2·3H2O (0.2 mmol) in DMF (5 mL) was stirred at 50 C for 6 h in
open air.
0
It is worthy to mention that the cyanation of 1a with benzoyl
cyanide to synthesize 2a could also be performed on gram-scale
and give the corresponding product in good yield (Scheme 2).
The reaction of 1.02 g of 1a with 1.31 g of benzoyl cyanide in 30
mL of DMF in the presence of 0.38 g of Cu(NO3)2·3H2O was
31
62
o
performed at 50 C for 20 h to give 2a in 68% yield (0.86 g)
78
isolated yield. The success of this gram scale reaction further
showed the potency of optimized condition for the bulk
processes.
a Reaction conditions: 1a (1 mmol), benzoyl cyanide (1 mmol), catalyst (0.2
b
c
mmol) in solvent (5 mL) was stirred for 6 h in open air. Isolated yield.
To illustrate the applications of propiolonitriles, some
functionalizations of 2a were implemented (Scheme 3). The

3
reactions of 2a with phenol, potassium iodide, or hydroxylamine
could smoothly synthesize Z-3-phenoxy-3-phenylacrylonitrile 3a
[13], Z-3-iodo-3-phenylacrylonitrile 4a [14] and 3-
phenylisoxazol-5-amine 5a [15]. These structures were
confirmed by comparison the analytical data with literatures.
These products are useful organic synthetic intermediates.
In summary, copper-catalyzed direct cyanation between
terminal alkynes and benzoyl cyanide to form propiolonitrile
under mild reaction conditions was developed. The salient
features of this protocol include use of less toxic, stable and easy
to handle cyanating agent, high yield and mild condition. This
method provides an efficient way to prepare propiolonitriles,
which are useful intermediates for many important organic
chemicals.
O
Cu(NO3)2
3H2O (0.38 g)
Air, DMF (30 mL), 50 oC, 20 h
CN
CN
H
+
Acknowledgements
2a
1a
(0.86 g, 68%)
(1.02 g)
(1.31 g)
The authors thank the National Natural Science Foundation of
China (21462038) for the financial support of this work.
Scheme 2 Gram-scale synthesis of 2a
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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Scheme 4 Proposed mechanism for 2a.
agent



Air as an oxidant
Mild condition
Up to 85% yield
Highlight

Less toxic, stable and easy to handle cyanating