Palladium-catalyzed cyanation reaction of aryl halides using K 4[Fe(CN)6] as non-toxic source of cyanide undermicrowave irradiation

Article abstract of DOI:10.1002/aoc.1639

An efficient method for preparation of aryl nitriles - using [Pd{C ₆H₂(CH₂CH₂ NH₂)-(OMe) ₂,3,4} (μ-Br)]₂ complex as an efficient catalyst and K₄[Fe(CN)₆] as a green cyanide source - from aryl bromides, aryl iodides and aryl chlorides under microwave irradiation has been reported. This complex has been demonstrated to be an active and efficient catalyst for this reaction.Using a catalytic amount of this synthesized palladium complex in DMF at 130 ° led to production of the cyanoarenes in excellent yields in short reaction times. Copyright

Full text of DOI:10.1002/aoc.1639

Full Paper
Received: 11 October 2009
Revised: 22 November 2009
Accepted: 2 February 2010
Published online in Wiley Interscience: 12 March 2010
(www.interscience.com) DOI 10.1002/aoc.1639
Palladium-catalyzed cyanation reaction of aryl
halides using K4[Fe(CN)6] as non-toxic source
of cyanide under microwave irradiation
Abdol R. Hajipoura,b∗ , Kazem Karamib and Azadeh Pirisedighb
An efficient method for preparation of aryl nitriles – using [Pd{C6H2(CH2CH2 NH2)-(OMe)2,3,4} (µ-Br)]2 complex as an efficient
catalyst and K4[Fe(CN)6] as a green cyanide source – from aryl bromides, aryl iodides and aryl chlorides under microwave
irradiation has been reported. This complex has been demonstrated to be an active and efficient catalyst for this reaction. Using
a catalytic amount of this synthesized palladium complex in DMF at 130 ◦C led to production of the cyanoarenes in excellent
c
yields in short reaction times. Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Keywords: K4[Fe(CN)6]; catalyst; cyanation reaction
Introduction
decrease of unwanted byproducts from thermal side-reactions.[34]
Microwave-mediated chemistry is often carried out in microwave-
active polar solvents such as N-methyl-2-pyrrolidone (NMP),
dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF).
The high dipole moment of these solvents means that they can
be heated very quickly using microwave irradiation. Alterman and
Hallberg have shown a pattern for using microwave heating to
raisetherateofcyanationofdifferentbromideswiththepreviously
utilized palladium–tetrakistriphenylphosphine.[35]
In continuation of our investigation of the new methods in
organic reactions,[36–40] herein we have employed orthopalladate
complex[Pd{C6H2(CH2CH2 NH2)-(OMe)2,3,4}(µ-Br)]2 forcyanation
reactions of various aryl halides under microwave irradiation using
K4[Fe(CN)6] as a cyanide source.
Thesubstitutedbenzonitrilesrepresentimportantmaterialsforthe
preparation of different commercial compounds, including dyes,
herbicides, pesticides, natural products and pigments.[1–7] The
cyanide functional group may be converted to other functional
groups such as carboxylic acids, amides, amines, aldehydes and
ketones;[8,9] therefore these compounds play significant roles in
modern organic synthesis. Furthermore in medical chemistry,
nitriles are very valuable, since they can be transformed to various
biologically active molecules such as terazoles, oxazoles and
triazoles.[10] Most often aryl nitriles are prepared from aryl halides
using stoichiometric amounts of CuCN by Rosenmund–Von Braun
reaction.[11] Thesecompoundshavebeenproducedindustriallyvia
amoxidation of the corresponding toluene derivatives[12] or from
aniline via diazotization followed by Sandmeyer reaction.[13,14]
The harsh reaction conditions and the use of stoichiometric Results and Discussion
amountsofcopper(I) cyanideleadstotheproductionofequimolar
Inthepreviouswork,[36] wesynthesizedcomplexAandreportedits
amounts of heavy metal wastes, especially in the case of
industrial large-scale synthesis, which is a major drawback of
these methods.[4,15] Since the mid 1970s the synthesis of aryl
nitriles through the cyanation of aryl halides, using transition
metal catalysts and employing inexpensive cyanide salts such as
KCN,[16,17] NaCN,[18,19] Me3SiCN[20–22] and Zn(CN)2, has become
more popular.[23–27]
The toxicity of KCN and NaCN, the sensitivity of Me3SiCN to
moisture, the release of HCN and production of heavy metal waste,
in the case of Zn(CN)2, significantly limit the applications of these
reagents. Thesedifficultieshavebeenovercomeusinginexpensive
and non-toxic potassium hexacyanoferrate (II), K4[Fe(CN)6], as an
efficient source of cyanide.[28–31]
In comparison to traditional Rosenmud–Von Braun nitrile
synthesis, nickel[32]- and palladium[33]-catalyzed methods have
been considered milder procedures; however these transition
metal-catalyzed reactions require several hours.[16] The use of
microwave irradiation in transition metal-catalyzed reactions,
which are usually time consuming, has assumed great importance
due to the reduction of the reaction times to minutes and the
application in the Heck reaction successfully. The main advantage
of this method is using microwave irradiation as a reaction
accelerator by investigating the synergy of microwave heating
with microwave active solvents and K4[Fe(CN)6] for cyanation of
several aryl halides (Scheme 1).
The application of complex A as a catalyst for the cyanation
reactionwasexaminedbyoptimizingbothbaseandsolventunder
microwave conditions [Table 1]. We treated 1-bromonaphtalene
with K4[Fe(CN)6] in the presence of different bases and solvents
(Table 1) and we found that K2CO3 is the best base for this
∗
Correspondence to: Abdol R. Hajipour, Pharmaceutical Research Laboratory,
Department of Chemistry, University of Technology, Isfahan 84156, Iran.
E-mail: haji@cc.iut.ac.ir
a
Department of Pharmacology, University of Wisconsin, Medical School, 1300
University Avenue, Madison, WI 53706-1532, USA
b
Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology, Isfahan 84156, I. R. Iran
c
Appl. Organometal. Chem. 2010, 24, 454–457
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

Palladium-catalyzed cyanation reaction of aryl halides
Table 3. Cyanation reaction of aryl halides with K4 [Fe(CN)6] using
catalyst Aa
Time
(min)
Yield
(%) b
Entry
1
Ar–X
Product
16
93
I
I
CN
CN
Scheme 1. Cyanation of aryl halides using K4[Fe(CN)6] under microwave
irradiation.
MeO
O2N
MeO
O2N
2
20
68
Table 1. Optimization of reaction condition in cyanation reaction of
bromonaphtalene with K4[Fe(CN)6
3
4
8
90
85
Br
CN
Catalyst,
Temperature Time Conversion
Entry Base
mol% Solvent
(◦C)
(min)
(%)
11
Br
Br
CN
CN
1
Et3N
Et3N
0.4
1
NMP
NMP
130
130
130
130
130
130
130
130
120
80
20
20
20
20
20
30
11
11
25
30
30
0
Trace
40
2
3
Na2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.4
1
NMP
5
6
25
20
73
94
4
NMP
50
5
0.4
1
NMP
50
6
NMP
80
7
0.4
1
DMF
60
8
DMF
90
O
O
H
9
0.4
0.4
0.4
DMAC
CH3CN
Toluene
50
H
10
11
0
CN
CN
Br
110
0
7
8
10
16
95
93
Br
NC
CN
Table 2. Optimization of catalystconcentration in cyanation reaction
of bromonaphtalene with K4[Fe(CN)6
O
O
O
H3C
H3C
H3C
Catalyst,
mol%
Time Temprature Conversion
Entry Base
Solvent (min)
(◦C)
(%)
Br
CN
9
20
20
57
O
1
2
3
4
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
DMF
DMF
DMF
DMF
DMF
20
20
20
11
13
130
130
130
130
130
0
20
40
90
90
CN
Br
0.1
0.2
0.5
0.8
H3C
10
Trace
O
O
CN
Br
H3C
H3C
11
12
20
15
0
reaction, while Et3N is not efficient and Na2CO3 produced only
50%arylcyanide. Themicrowave-inactivesolventssuchastoluene
and acetonitrile were not suitable (Table 1, entries 10 and 11).
Therefore we tried high boiling point and microwave-active polar
solvents (Table 1, entries 1–9) and found that inexpensive and
readily available DMF showed the best results (Table 1, entries 7
and 8). Also, we optimized the catalyst concentration (Table 2) and
0.5 mol% gave the best yields.
Using 0.5% palladacycle and a 1 : 1 molar ratio of 1-bromo-
naphtalene to K4[Fe(CN)6] conversion to the corresponding
cyanideoccurredin90%yield. AseachmolofK4 [Fe(CN)6]contains
six-fold cyanide ions, decreasing the ratio of K4[Fe(CN)6 to aryl
halide to 0.2 : 1 did not decrease the reaction conversion.
CN
N
N
Br
50
O
O
H
H
CN
CI
13
14
25
20
24
58
O
O
H3C
H3C
CN
CI
CI
CI
We employed the optimal reaction conditions (aryl halide,
1 mmol; K4[Fe(CN)6], 0.2 mmol; K2CO3, 1 mmol; and DMF as
the best reaction media) for cyanation of different aryl halides
and the results are demonstrated in Table 3. We found that
different aryl halides such as aryl bromides (Table 3, entries
3–9), aryl iodides (Table 3, entries 1 and 2), were converted
to the corresponding aryl cyanide under these conditions. The
CN
Br
•
a Reaction conditions: aryl bromide; 1 mmol, K4 [Fe(CN)6] 3H2O;
0.22 mmol, K2CO3; 1 mmol, catalyst A; 0.005 mmol, temperature;
130 ◦C.
b Isolated yield.
c
Appl. Organometal. Chem. 2010, 24, 454–457
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc

A. R. Hajipour, K. Karami and A. Pirisedigh
aryl bromides with electron-withdrawing groups (Table 3, entries
6–8) were cyanated efficiently. However, 3-bromoacetophenone
transformed to cyano derivative in moderated yield (Table 3,
entry 9) and 2-bromoacetophenone remained unchanged after
20 min (Table 3, entry 10); also, electron neutral aryl bromides
(Table 3, entries 3–5) were changed to desired cyanoarenes,
but 2-bromopyridine was not converted to 2-cyanopyridine
(Table 3, entry 11). The chemoselectivity of this method was
examined by cyanation of 1-bromo-3-chlorobenzene to 1-chloro-
3-cyanobenzene (Table 3, entry 12); however the aryl chlorides
were converted to the cyanoarenes in low to moderate yields
(Table 3, entries 13 and 14).
Naphthalene-1-carbonitrile (entry 2, Table 3)
M.p 36–38 ◦C;[25] found 36–39 ◦C. 1H NMR (400 MHz, CDCl3):
δ = 8.19 (d, 1H, J = 8.5 Hz), 8.03 (d, J = 8.8 Hz, 1H), 7.87 (t,
J = 8.8 Hz, 2H), 7.55–7.68 (m, 2H), 7.47 (t, J = 8.8 Hz, 1H). 13C
NMR (400 MHz, ppm, CDCl3): δ = 132.2, 131.8, 131.5, 131.2, 127.6,
127.5, 126.5, 124.0, 123.8, 109.2. IR (KBr, cm−1): ν 2222.
3-Chlorobenzonitrile (entry 3, Table 3)
◦
1
M.p. 136–140 C; H NMR (400 MHz, CDCl3): δ = 7.96–7.97 (m,
1H), 7.89–7.92 (m, 1H), 7.63–7.68 (m, 1H), 7.58–7.59 (m, 1H); 13C
NMR (400 MHz, ppm, CDCl3): δ = 136.2, 135.6, 132.0, 130.6, 117.8,
117.4, 102.1. IR (KBr, cm−1): ν 2215.
Conclusion
4-Acetylbenzonitrile (entry 4, Table 3)
Inthisinvestigation,wehavedevelopedafastandefficientmethod
for the conversion of aryl halides to cyanoarenes using non-toxic
potassium hexacyanoferrate(II) instead of toxic alkali cyanides as
a green chemistry method using microwave irradiation with high
yields and short reaction times. Employing a catalytic amount
of palladacycle complex converted different aryl bromides and
iodides to the corresponding benzonitriles in high yields, but aryl
chlorides were changed to benzonitriles with moderate yields. In
comparison to conventional thermal conditions, these reactions
were completed in shorter reaction times (8–25 min).
M.p. 57–58 ◦C;[25] found 59–60 ◦C. 1H NMR (400 MHz, CDCl3):
δ = 8.06 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.4 Hz). IR (KBr, cm−1):
ν 2229, 1687.
4-Methoxybenzonitrile (entry 7, Table 3)
M.p. 59–60 ◦C;[25] found 58–60 ◦C; 1H NMR (400 MHz, CDCl3):
δ = 7.57–7.60 (m, 2H), 6.94–6.97 (m, 2H), 3.86 (s, 3H); 13C NMR
(400 MHz, ppm, CDCl3): δ = 163.1, 134.2, 127.9, 115.0, 114.4, 55.8.
IR (KBr, cm−1): ν 2218.
Experimental
Phenantrene-9-carbonitrile (entry 9, Table 3)
M.p. 88–92 ◦C. 1H NMR (400 MHz, CDCl3): δ = 8.73 (t, 2H,
J = 8.4 Hz), 8.33 (d, 1H, J = 8.4 Hz), 8.28 (s, 1H), 7.96 (d, 1H,
J = 8 Hz), 7.76–7.85 (m, 3H), 7.70 (t, 1H, J = 7.6 Hz). 13C NMR
(400 MHz, ppm, CDCl3): δ = 135.9, 130.1, 129.9, 129.7, 129.4,
128.6, 128.4, 127.9, 126.2, 123.1, 123.4, 101.5. IR (KBr, cm−1): ν
2219.
General
All melting points were taken on a Gallenkamp melting apparatus
and are uncorrected. 1H-NMR spectra were recorded using 500
and 400 MHz in CDCl3 solutions at room temperature (TMS was
used as an internal standard) on a Bruker, Avance 500 instrument
(Rheinstetten, Germany) and Varian 400 NMR. FT-IR spectra were
recorded on a spectrophotometer (Jasco-680, Japan). We used
a Milestone microwave (Microwave Labstation for synthesis).
Homoveratrylamine, palladium acetate, all of the aryl halides
and K4[Fe(CN)6] were purchased from Merck and Aldrich and used
as received.
Acknowledgments
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), Isfahan
Science & Technology Town (ISTT), I. R. Iran. Further financial
support from the Center of Excellence in Sensor and Green
Chemistry Research (IUT) is gratefully acknowledged
Typical Procedure for the Cyanation Reaction of Aryl Halides
with K4[Fe(CN)6]
Ina10 mlround-bottomedflaskwereplacedarylhalide(1.0 mmol),
potassium hexacyanoferrate(II) (0.2 mmol), potassium carbonate
(1.0 mmol) and palladacycle A (which was synthesized as in a
previous work[36]), 0.5 mol%. After adding DMF (2 ml), the round-
bottomed flask was equipped with a condenser and placed into
the Milestone microwave. Initial microwave irradiation of 500 W
was used, the temperature being ramped from room temperature
to the desired temperature of 130 ◦C with stirring. The reaction
mixture was held at this temperature until the reaction was
completed (TLC, EtOAc : cyclohexane, 25 : 75) and then cooled to
room temperature. The mixture was diluted with water (30 ml)
and extracted with ethyl acetate (30 ml). The organic layer was
dried over MgSO4 and the solvents were evaporated using rotary
evaporator to produce crude product. The residue was purified by
silica gel column chromatography to provide the pure products
(Table 3).
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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