Microwave assisted ligand free palladium catalyzed synthesis of β-arylalkenyl nitriles using water as solvent

Article abstract of DOI:10.1007/s10562-010-0279-2

We have developed a rapid and efficient method for the synthesis of β-arylalkenyl nitriles by one pot three component coupling reaction of diphenyl acetylene, K₄(Fe)CN₆, and aryl halides using Pd(OAc)₂ as a catalyst and water as a solvent under microwave irradiation. The method is very simple and attractive as it requires only a shorted reaction time and employs cyanide source which is safe and inexpensive. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-010-0279-2

Catal Lett (2010) 135:148–151
DOI 10.1007/s10562-010-0279-2
Microwave Assisted Ligand Free Palladium Catalyzed Synthesis
of b-Arylalkenyl Nitriles Using Water as Solvent
•
Sivan Velmathi Reena Vijayaraghavan
•
•
Ravindra P. Pal Ajayan Vinu
Received: 13 November 2009 / Accepted: 18 January 2010 / Published online: 4 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract We have developed a rapid and efficient
method for the synthesis of b-arylalkenyl nitriles by one
pot three component coupling reaction of diphenyl acety-
lene, K4(Fe)CN6, and aryl halides using Pd(OAc)2 as a
catalyst and water as a solvent under microwave irradia-
tion. The method is very simple and attractive as it requires
only a shorted reaction time and employs cyanide source
which is safe and inexpensive.
range of natural products, dyes, agrochemicals and phar-
maceutically active compounds [5, 6]. They are also
valuable intermediates in organic synthesis and can be
easily transformed into acids, esters, amides and amines. A
number of synthetic methods for the preparation of aryl
nitriles have been developed including the direct cyanation
of aryl halides by copper (I) cyanide, known as Rosen-
mund–von Braun reaction [7, 8]. The classical Rosen-
mund–von Braun procedure requires harsh reaction
conditions, making it incompatible with sensitive sub-
strates. While modifications to this procedure have been
made, transition metal catalyzed aryl cyanation approaches
show more promise [9]. A disadvantage with these proto-
cols was that toxic inorganic or organic cyanide sources
such as alkali metal cyanides trimethylsilyl cyanide or
acetone cyanohydrin are often required. However, this has
been overcome by the use of a cheap and a non-toxic
K4[Fe(CN)6] as a cyanide source [10]. This has generated
several methodologies including the method involves the
ligand-free palladium sources [11–15]. Recently Lead-
beater et al. [16] have reported a methodology for the
cyanation of aryl iodides and activated aryl bromides using
water as the solvent and K4[Fe(CN)6] as the cyanide
source.
Keywords Aryl halides ꢀ Diphenylacetylene ꢀ
b-Alkenyl nitriles ꢀ K4Fe(CN)6 ꢀ Microwaves ꢀ
Palladium acetate
1 Introduction
Carbon–carbon bond forming reaction has always been one
of the most important fundamental reactions in organic
chemistry [1]. A variety of transition metals including
palladium [2], copper [3] or nickel [4] has been used as the
catalysts for the coupling reactions like Heck, Sonagashira
and provided a powerful tool for C–C bond formation.
Similarly aryl nitriles represent an important class of
compounds since the functionality is widely found in a
Reactions are completed within 20 min microwave
heating at the reaction temperature of 150 °C. Similarly,
there have been several reports regarding the Palladium
catalyzed alkenylation of aryl halides [17]. However, only
a few reports are available in the area of Palladium cata-
lyzed three component coupling reaction with aryl halides,
alkynes and cyanides which lead to the synthesis of
substituted b-arylalkenyl nitriles. The first report on pal-
ladium catalyzed three component aryl cyanation of
internal alkynes with aryl bromides and K4[Fe(CN)6] was
done by Wu et al. [11]. The reaction required 2 mol% of
S. Velmathi (&) ꢀ R. Vijayaraghavan
Organic and Polymer Synthesis Laboratory,
Department of Chemistry, National Institute of Technology,
Tiruchirappalli, Tamil Nadu 620 015, India
e-mail: velmathis@nitt.edu
S. Velmathi ꢀ R. P. Pal ꢀ A. Vinu
International Center for Materials Nanoarchitectonics,
World Premier International (WPI) Research Initiative,
National Institute for Materials Science, Tsukuba,
Ibaraki 305-0044, Japan
123

Microwave Assisted Ligand Free Palladium
149
Pd(OAc)2, 1 equivalent of Na2CO3 and a reflux tempera-
ture of 120 °C for 5 h in dimethylacetamide (DMAc)
solvent. Accordingly, the development of more efficient
methods is still in demand. In addition, high-density
microwave heating has become an effective procedure
because it allows rapid and convenient superheating to
high temperatures in combination with excellent reaction
control and low energy consumption. It has been proven
recently that microwave heating improves the preparative
efficiency and reduces the reaction time for several dif-
ferent types of organic transformations [18, 19]. In the
past few years, the utilization of microwave irradiation in
organic synthesis has become increasingly popular within
the pharmaceutical and academic arenas [20]. By taking
advantage of this efficient source of energy, compound
libraries and optimization can be assembled in a fraction
of the time required by classical thermal methods [21].
Microwave-assisted protocols have been widely applied to
the formation of a variety of carbon-heteroatom and car-
bon–carbon bonds [22–25]. As a part of our ongoing
research in the area of microwave assisted organic syn-
thesis [16, 26], we present the microwave assisted cya-
nation of internal alkynes with aryl halides using water as
solvent. To the best of our knowledge this is the first
report on the microwave assisted synthesis of b-alkenyl
nitriles.
organic washings were combined and dried them using
anhydrous Na2SO4. Finally, the ether was removed in
vacuum leaving the crude product which was then isolated
by silica gel column chromatography with 3% ethyl acetate
1
in petroleum ether and characterized by H, 13C NMR and
Mass spectral data. NMR spectra were obtained using
Bruker 400 MHz instrument using DMSO as the solvent
with chemical shifts relative to TMS. LCMS analysis were
carried out using Agilent Ion Trap LCMS 6330 fitted with a
Ascentis C 18 (5 cm 9 4.6 mm 9 2.7 micron) column,
Flow rate of 0.6 mL/min, Mobile phase: Acetonitrile:water
(1:1). GCMS analysis were done with Agilent Model
6890 N-5973 fitted with the DB1 MS (30 m 9 0.32 mm 9
0.25 lm) Column.
2.1 Characterization Data
Compound 1a (Z)-2,3-diphenyl-3-(4-acetyl phenyl) acry-
1
lonitrile H NMR (400 MHz, CDCl3) d ppm: 2.63 (s, 3H),
6.9 (m, 2H), 7.0 (m, 2H), 7.1–7.27 (m, 3H), 7.4 (m, 1H),
7.5 (d, 1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.1 (d, 2H) 13C
NMR(100 MHz, CDCl3): 29.5, 110.2, 118.8, 126.2, 126.4,
128.0, 128.7, 134.3, 135.9, 140.2, 144.4, 151.5, 199.7 mass
(m/z): 323, 308, 280, 264, 253, 239, 207, 191.
Compound 1b p-(2-cyanao-1,2-diphenylvinyl)anisole:
1H NMR (400 MHz, CDCl3) d ppm: 3.8 (s, 3H), 6.9 (m,
2H), 7.0 (m, 2H), 7.15–7.25 (m, 8H), 7.45 (m, 2H) 13C
NMR (100 MHz, CDCl3): 55.8, 108.7, 114.2, 118.2, 121.2,
126.4, 127.4, 128.0, 128.7, 130.6, 131.6, 132.3, 134.3,
140.8, 157.5, 159.8. MS (m/z): 311, 281, 253, 207, 178,
163, 152.
2 Experimental
Typical procedure for the cyanation of internal alkynes
with aryl halides and K4[Fe(CN)6]: In a Teflon coated
vessel, 4-iodoacetophenone (615 mg, 2.5 mmol), diphen-
ylacetylene (356 mg, 2 mmol), K4Fe(CN)6 (232 mg,
0.55 mmol), sodium fluoride (104 mg, 2.5 mmol), tetra-
butylammonium bromide (805 mg, 2.5 mmol), and
Pd(OAc)2 (28 mg, 0.125 mmol) were placed. After adding
water (15 mL), the vessel was sealed and placed into the
microwave cavity (Milestone Multisynth). Initial micro-
wave irradiation of 150 W was used, the temperature being
ramped from RT to the desired temperature of 150 °C
(measured using the built-in IR temperature device). Once
the target temperature was reached, the reaction mixture
was held at this temperature until a total time of 20 min
had elapsed. During this time, the power was modulated
automatically to hold the reaction mixture at 150 °C. The
mixture was not stirred during the reaction. After allowing
the mixture to cool to room temperature, the reaction vessel
was opened and the contents poured into a separating
funnel. Water (30 mL) and diethyl ether (30 mL) were
added, and then the organic material was extracted and
removed. After further extraction of the aqueous layer, the
Compound 1c p-(2-cyanao-1,2-diphenylvinyl)aniline:
1H NMR (400 MHz, CDCl3) d ppm: 7.01 (d, 2H), 7.12 (d,
2H), 7.2–7.3 (m, 8H), 7.4 (d, 2H), 5.2 (bs, 2H) 13C NMR
(100 MHz, CDCl3): 96.7, 116.2, 118.2, 126.4, 127.2,
128.0, 128.7, 130.0, 134.3, 140.8, 149.6, 155.5 MS (m/z):
296, 281, 253, 239, 207, 180.
Compound 1d o-(2-cyanao-1,2-diphenylvinyl)anisole:
1H NMR (400 MHz, CDCl3) d ppm: 3.8 (s, 3H), 6.9 (m,
2H), 7.0 (m, 2H), 7.15–7.25 (m, 8H), 7.45 (m, 2H) 13C
NMR (100 MHz, CDCl3): 56.2, 109.2, 112.9, 114.2, 118.5,
121.2, 126.4, 127.4, 128.0, 128.7, 129.0, 130.6, 132.3,
134.3, 140.0, 151.5, 158.8 MS (m/z): 311, 281, 253, 207,
178, 163, 152.
Compound 1e (Z)-2,3-diphenyl-3-(1-Naphthalene)
acrylonitrile 1H NMR (400 MHz, CDCl3) d ppm: 7.1–7.25
(m, 5H), 7.27–7.32 (m, 3H), 7.4–7.5 (m, 4H), 7.6–7.7 (m,
2H), 7.8 (d, 1H), 7.92 (d, 1H), 8.0 (d, 1H), 13C NMR
(100 MHz, CDCl3): 113.7, 118.8, 126.0, 126.4, 123.5,
125.0, 127.7, 128.1, 128.0, 128.2, 128.7, 133.2, 133.6,
134.3, 138.4, 140.8, 151.5. MS (m/z): 331, 304, 281, 253,
226, 207, 191, 150.
123

150
S. Velmathi et al.
Scheme 1 Aryl cyanation of
diphenylacetylene with aryl
halides
Pd(OAc)2
R'
R'
NaF, TBAB
+
X
+ K4Fe(CN)6
R
R
H2O, MW,
150o C, 20 min
C N
3 Results and Discussion
follows: aryl halide (1 mmol), diphenylacetylene
(0.75 mmol), K4Fe(CN)6 (0.15 mmol) NaF (1 mmol), tet-
rabutylammonium bromide (TBAB) (1 mmol), Pd(OAc)2
(5 mol %), water (15 mL), reaction temperature of 150 °C,
and total time of 20 min (Scheme 1).
Initially we studied the coupling reaction of 4-iodoaceto-
phenone (1.5 eq), diphenylacetylene (1 eq) K4Fe (CN)6
(0.22 eq), Pd(OAc)2 (2 mol%), Na2CO3 (1 eq) in dimeth-
ylacetamide (Scheme 1) under Microwave irradiation at
150 °C for 20 min following the reported procedure except
for the change in heating mode, the reaction temperature
and the reaction time. Surprisingly, the NMR spectrum of
the crude product revealed the decomposition of starting
compounds and no trace of the formation of the product
(Table 1, entry-1). Changing the solvent to DMF also did
not make any change in the formation of the products
either. Sodium carbonate which is proved to be an efficient
base in organic solvents did not yield any of the coupling
products in water medium. Therefore, we investigated the
role of different bases and found that NaF was able to
catalyze the reaction and yield the desired product in 60%.
When the reaction was conducted in a polar solvent like
ethanol or acetone only marginal yield of the product
(Table 1, entry-5, 6) was obtained. Rise in the reaction
temperature from 150 to 170 °C resulted in decomposition
of the starting materials. Also increasing the reaction time
from 10 to 30 min does not result in increased yield. The
results obtained out of the preliminary studies are given in
Table 1 and the optimal reaction condition was derived
from the data. The optimum reaction condition is as
A number of aryl halides have also been screened and
the results are shown in Table 2. From the table it can be
seen that both aryl bromides and aryl iodides were equally
reactive in the coupling reaction. Aryl halides bearing both
electron releasing and withdrawing substituents were found
to react to give moderate to good yield of arylalkenyl
nitriles. Reported low yield in all the cases was due to the
fact that both the aryl halides and diphenylacetylene were
not completely reacted. GC–MS analysis of the crude
reaction mixture indicated the presence of starting mate-
rials and the desired coupled product and no trace of aryl
nitriles were observed. Ortho substitution hampered the
reaction yield compared to para substituents (Table 2 entry
6). The present protocol provides a direct method for the
synthesis of b-arylalkenyl nitriles, important intermediate
of biologically active compounds and organic materials
[27].
4 Conclusion
In conclusion, we have developed a rapid and efficient
method for the synthesis of b-arylalkenyl nitriles by one pot
three component coupling reaction of diphenylacetylene,
Table 1 Palladium catalyzed cyanation of 4-iodoacetophenone with
diphenylacetylene
Solvent Time (min) Temp. (°C) Yield (%)a
Table 2 Palladium catalyzed aryl cyanation of diphenylacetylene
with aryl halides
S. no. Base
1
2
Na2CO3 DMF
20
20
20
20
20
150
150
150
150
150
150
150
150
150
170
–
S. no. Compound no. ArX
R
Product
R
Yield
(%)a
Na2CO3 DMAc
Na2CO3 Waterb
–
R0
X
I
R0
3
–
4
K2CO3
NaF
NaF
NaF
NaF
NaF
NaF
DMF
–
1
2
3
4
5
6
7
1a
1a
1b
1b
1c
1d
1e
COMe
COMe
OCH3
OCH3
NH2
H
COMe
H
H
H
H
H
67
60
68
62
58
5
Water
60
15
Trace
40
60
–
H
Br COMe
OCH3
Br OCH3
6
Ethanol 20
Acetone 20
H
I
7
H
8
Water
Water
Water
10
30
20
H
I
I
I
NH2
H
9
H
OCH3
H
OCH3 45
69
10
Ph
Ph
H
Aryl halide (1 mmol), diphenylacetylene (0.75 mmol), K4Fe(CN)6
(0.15 mmol), Pd(OAc)2 (5 mol %) were used in all the cases
Reaction conditions: aryl halide (1 mmol), diphenylacetylene
(0.75 mmol), K4Fe(CN)6 (0.15 mmol) NaF (1 mmol), TBAB
(1 mmol), Pd(OAc)2 (5 mol %), water (15 mL), reaction temperature
of 150 °C, and total time of 20 min
a
Isolated yield
b
Whenever water was used in the reaction 1 mmol of TBAB was
also used
a
Isolated yield
123

Microwave Assisted Ligand Free Palladium
151
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K4(Fe)CN6, and aryl halides. The use of Pd(OAc)2 as cat-
alyst, water as solvent and safe and cheap cyanide source of
K4(Fe)CN6 makes this method attractive. In addition, the
microwave irradiation helps us to reduce the reaction time
significantly which makes the method simpler and could
lead the path to the commercialization. Efforts for the
expansion of the scope of this reaction especially to
improve the yield and stereoselectivity of the reaction are
under progress.
Acknowledgments One of the authors S.V gratefully acknowledges
the support and funding from Dr. M. Chidambaram, the Director of
NITT and DST (SR/FTP/CS-142-2006). This work was also partially
supported by the Ministry of Education, Culture, Sports, Science and
Technology (MEXT) under the Strategic Program for Building an
Asian Science and Technology Community Scheme and World Pre-
mier International Research Center (WPI) Initiative on Materials
Nanoarchitectonics, MEXT, Japan.
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