Direct synthesis of 3-halo-3-arylacrylonitriles from the addition of cyanoalkynes with alkaline metal halides

Article abstract of DOI:10.1016/j.tetlet.2017.07.104

An efficient synthesis of 3-halo-3-arylacrylonitrile is described from the direct addition between cyanoalkynes and inorganic alkaline metal halides such as LiCl, LiBr and KI in good to satisfactory yields. No transition metal is needed for the synthesis

Full text of DOI:10.1016/j.tetlet.2017.07.104

Accepted Manuscript
Direct Synthesis of 3-Halo-3-arylacrylonitriles from the Addition of Cyanoal-
kynes with Alkaline Metal Halides
Zhipeng Guan, Zhiwen Liu, Wei Shi, Hao Chen
PII:
S0040-4039(17)30972-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.104
TETL 49186
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 June 2017
28 July 2017
29 July 2017
Please cite this article as: Guan, Z., Liu, Z., Shi, W., Chen, H., Direct Synthesis of 3-Halo-3-arylacrylonitriles from
the Addition of Cyanoalkynes with Alkaline Metal Halides, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.07.104
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Direct Synthesis of 3-Halo-3-arylacrylonitriles from the
Addition of Cyanoalkynes with Alkaline Metal Halides
Zhipeng Guan, Zhiwen Liu, Wei Shi* and Hao Chen*
College of Science, Huazhong Agricultural University, Wuhan, China.
Abstract
An efficient synthesis of 3-halo-3-arylacrylonitrile is described from the direct addition
between cyanoalkynes and inorganic alkaline metal halides such as LiCl, LiBr and KI in good
to satisfactory yields. No transition metal is needed for the synthesis of iodo- and bromo-
products, although Pd catalyst is used to accelerate the chloro- product.
Key words:
Cyanoalkyne, 3-halo-3-arylacrylonitrile, addition of alkyne.
3-Halo-3-arylacrylonitriles represent one of the important building blocks in
organic synthesis due to the reactivity of halogens, nitriles and alkenyl moieties in a
number of chemical transformations1-7 (Figure 1). On the other hand, the cyano group
has always been envisaged as a fountain head of functionalization in organic and
medicinal chemistry due to its facile transformation to functional groups of medicinal
significance such as amines, amides, amidines, aldehydes, ketones, carboxylic acids,
esters etc., many of which have already been used as its bioisosteres4. Thus the
synthesis of 3-halo-3-arylacrylonitrile is of great importance in organic and
bioorganic chemistry area.
Figure 1. Derivations of 3-halo-3-arylacrylonirile

As far as we know, there are only limited reports focuses on the synthesis of
β-halo-α, β-unsaturated nitriles1, 8, 9. One typical procedure was reported by Ohe and
co-workers, using Gallium catalyzed bromocyanation of alkynes by BrCN1. Although
high regio- and stereoselectivities were obtained, only moderate yields were observed
in most cases. Based on our previous studies on cyanoalkynes, including the
preparation6 and addition of this structure10, we assumed that the addition of
cyanoalkynes with halogenating reagents may also lead to the β-halo-α, β-unsaturated
nitriles, as shown in Figure 2, and following explorations have supported this idea. By
using cheap, easily available and handling alkaline metal halide salts such as KI, LiBr
or LiCl, 3-halo-3-arylacrylonitriles could be obtained in good to excellent yields, with
high regio- and stereoselectivities. Herein, we wish to report our latest discoveries,
providing an efficient and new route to these important compounds.
Figure 2. Synthetic route to 3-halo-3-arylacrylonitriles
Ohe's work
This work
X
+
+
MX
M = Li, K
R
X CN
R
CN
CN
R
Inspired by the work of Jiang11, we initiated our exploration from the addition of
inorganic salt KI to 3-(p-tolyl)propiolonitrile (1a) in Ac2O, aiming to achieve the
3-iodo-3-(p-tolyl)acrylonitriles (2a). It is noteworthy that this compound has not been
reported yet. However, only 27% of 2a was obtained (Entry 1, Table 1). Other polar
solvents, including DMF, DMSO or NMP did not show any improvement. Excellent
result was observed while HOAc was employed as the solvent instead of Ac2O (Entry
6, Table 1). This may attribute to the better solubility for inorganic salts and
protonation property of the protic solvent. Moreover, only the less sterically hindered
Z- isomer was observed by GC, indicating that this method was highly regio- and
stereoselective. Optimized condition was listed as entry 10, using 1.5 eq. KI and
HOAc as the solvent under 120 oC in 2 hours (Entry 9, Table 1).
Table 1. Optimization of the reaction conditions

o
With the optimized reaction conditions established (1.5 eq. KI in HOAc at 120 C
for 2 h), we then investigated the reactivity of other 3-propiolonitriles. Moderate to
excellent isolated yields (10 examples, up to 99%) were observed. Both
electron-donating group and electron-withdrawing group can be tolerated. Ortho - and
meta-substituents on the phenyl ring of the 3-propiolonitriles could both be tolerated
and gave acceptable yields. Moreover, heterocyclic substrate was proved to be good
reactant, with a surprisingly high isolated yield of 99% (2j). It is also noteworthy that
the reaction may still work well in gram scale synthesis. 90% isolated yield was
observed for 2e when 5 mmol of substrate was employed.
Table 2. Substrate scope for the synthesis of 3-iodo-3-arylacrylonitriles

Encouraged by the achievements employed with KI, we have then tested the
activity of KBr reacting with 3-phenylpropiolonitrile (Table 3). However, certain loss
o
of the yield was observed. By slightly lowering down the temperature to 110 C, only
moderate yield (77%) was observed for (Z)-3-bromo-3-phenylacrylonitrile (Entry 1,
Table 3). To promote the yield of the product, other alkali metal bromides were tested,
and to our delight, LiBr was proved to be more effective (Entry 2, Table 3). Reducing
o
the temperature did slow down the reaction, and 110 C was chosen to the further
experiments with different substrates.
Table 3. Optimization of the reaction conditions

We then employed LiBr to the synthesis of (Z)-3-bromo-3-arylacrylonitriles and the
results are shown in Table 4. Gratifyingly, good to excellent yields were obtained
again under this condition. Only Z- isomers were observed by GC, showing the
excellent regio- and stereoselectivity of this procedure again. The electronic
properties or position of the substituents connecting to the phenyl ring in
cyanoalkynes exhibited no obvious effects to the yields of the products. Gram scale
synthesis of 3a was also conducted, with a 83% isolated yield when 5 mmol of
substrate was used.
Table 4. Substrate scope for the synthesis of β-bromo-α, β-unsaturated nitriles

Furthermore, we have tried the synthesis of (Z)-3-chloro-3-arylacrylonitriles under
the same condition with the replacement of LiBr to LiCl. However, only 34% of the
product was obtained. Further investigation of the solvent effect did not show any
improvements (entries 1-6, Table 5). This may attribute to the relatively much less
weaker nucleophilicity of the chloride ions. Considering about the role the Palladium
catalysts play in the nucleophilic addition of alkyne moieties, different Pd catalyst
precursors were employed to advance the reaction, and positive data were observed,
as shown in entries 8-11, Table 5. We supposed that the Pd catalyst could coordinate
with the alkyne moiety, thus accelerate the nucleophilic addition from the chloride
ions. The best result (87%) was achieved when Pd(OAc)2 was used as the catalyst and
10% of 1,5-cyclooctadiene12 was added as the ligand (entry 11, Table 5).
Table 5 Optimization of the reaction conditions

With this optimized reaction conditions in hand, the scope of this Pd-catalyzed
addition reaction had been conducted, and the results are listed in Table 6. For most of
the substrates, mild to good isolated yields of the addition product were obtained.
More importantly, halogen atoms such as fluorine, bromine, and chlorine atoms on
the aromatic ring can be tolerated, affording the corresponding products in moderate
to good yields, with excellent regio- and stereoselectivities again. Gram scale
experiment was also carried out for 4a, with a 67% isolated yield using 5 mmol of
substrate.
Table 6. Substrate scope for the synthesis of β-chloro-α, β-unsaturated nitriles

In summary, we have developed a novel and efficient method for the synthesis of
β-halo-α, β-unsaturated nitriles through the addition of cyanoalkynes with cheap and
easy-handling inorganic halogenated alkaline metal salts. I-, Br-, as well as Cl-, were
all achieved in this procedure. The method exhibited excellent regio- and
stereoselectivities, as well as good functional group compatibility. Considering about
the importance of the β-halo-α, β-unsaturated nitriles in organic synthesis, this
procedure would have great meaning to organic synthesis.
Acknowledgement:
This work was supported by the National Natural Science Foundation of China
(NSFC) (51572101, 21202050) and the Natural Science Foundation of Hubei
Province of China (2014CFB930).
References:
1. Murai, M.; Hatano, R.; Kitabata, S.; Ohe, K., Chem. Commun. 2011, 47,
2375-2377.

2. Romagnoli, R.; Baraldi, P. G.; Remusat, V.; Carrion, M. D.; Cara, C. L.;
Preti, D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.;
Balzarini, J.; Jordan, M. A.; Hamel, E., J. Med. Chem. 2006, 49, 6425-6428.
3. Sahner, J. H.; Empting, M.; Kamal, A.; Weidel, E.; Groh, M.; Boerger, C.;
Hartmann, R. W., Eur. J. Med. Chem. 2015, 96, 14-21.
4. Sharma, P. K.; Ram, S.; Chandak, N., Adv. Synth. Catal. 2016, 358, 894-899.
5. Chinchilla, R.; Najera, C., Chem. Rev. 2014, 114, 1783-1826.
6. Brand, J. P.; Waser, J., Chem. Soc. Rev. 2012, 41, 4165-4179.
7. Fang, G.; Bi, X., Chem. Soc. Rev. 2015, 44, 8124-8173.
8. Liebscher, J.; Neumann, B.; Hartmann, H., J. Prakt. Chem. 1983, 325,
915-918.
9. Norman, M. H.; Chen, N.; Han, N.; Liu, L.; Hurt, C. R.; Fotsch, C. H.;
Jenkins, T. J.; Moreno, O. A. WO9940091A1, 1999.
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119-121.
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5796-5798.

Table 1
a
Entry
Solvent
T/℃
t/h
Yield (%) b
1
2
3
4
5
6
7
8
Ac2O
DMF
120
120
120
120
120
120
100
60
6
6
6
6
6
6
6
6
27
3
DMSO
NMP
None
None
None
99
1,4-dioxane
HOAc
HOAc
89
HOAc
15
9
HOAc
120
2
98
aReaction condition: 1 (0.5 mmol), solvent (2 mL).
bGC yield.

product
isolated yield
product
isolated yield
2a 93%
2f 97%
2b 72%
2c 95%
2g 59%
2h 83%
2d 71%
2e 86%
2i 66%
2j 99%

Table 3
a
Entry
T/℃
Bromide
Yield (%) b
1
2
3
4
5
110
110
110
80
KBr
LiBr
NaBr
LiBr
LiBr
77
88
52
80
43
50
aReaction condition: 1a' (0.5 mmol), bromide (0.75 mmol), solvent (2 mL),
bGC yield.

product isolated yield
product
isolated yield
3a 85%
3e 73%
3b 89%
3c 91%
3f 88%
3g 97%
3h 78%
3d 92%

Ta
ble 5
a
Entry
Catalyst (equiv.)
Solvent T/℃
Yield (%) b
1
2
3
4
5
6
7
8
-
Ac2O
DCE
110
70
23
-
None
None
Trace
None
None
34
-
DMSO
DMF
THF
110
110
60
-
-
-
-
EAC
70
HOAc
HOAc
110
110
PdCl2
43
9
Pd(OAc)2
[(Allyl)PdCl]2
Pd(Oac)2
HOAc
HOAc
HOAc
110
110
110
68
48
87
10
11 c
a Reaction condition: 1 (0.5 mmol), catalyst (0.025 mmol), LiCl (0.75
mmol), solvent (2 mL). b GC Yield. c 1,5-Cyclooctadiene (0.05
mmol) as a Ligand.

Table
6
product
product
isolated yield
isolated yield
4a 89%
4f 71%
4g 78%
4h 86%
4b 48%
4c 67%
4i 66%
4j 65%
4d 61%
4e 72%

Highlights:
ꢀ
An efficient synthetic route to 3-halo-3-arylacrylonitriles (including Cl-, Br- and I-) is
described.
ꢀ
ꢀ
ꢀ
High regio- and stereoselectivity is achieved, only Z- isomers are observed.
Halogen atoms are sourced from readily available inorganic salts.
First systematic study on the addition of cyanoalkynes with metal halides.

Synthetic pathway towards 3-halo-3-arylacrylonitriles with high efficiency,
versatility and excellent regio- and stereoselectivity.