An efficient palladium catalytic system for microwave assisted cyanation of aryl halides

Article abstract of DOI:10.1016/j.jorganchem.2010.10.002

Application of a new catalytic system for cyanation reaction of various aryl halides using K₄[Fe(CN)₆] as cyanating source was examined. The reactions were performed under microwave irradiation and results showed that application of this catalytic system and DMF at 130 °C minimized the reaction times from hours to minutes in good to excellent yields.

Full text of DOI:10.1016/j.jorganchem.2010.10.002

Journal of Organometallic Chemistry 696 (2011) 819e824
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
An efficient palladium catalytic system for microwave assisted cyanation
of aryl halides
a
,
b
,
b
b
b
*
Abdol R. Hajipour
, Kazem Karami , Ghazal Tavakoli , Azade Pirisedigh
a
Department of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue, Madison, 53706-1532 WI, USA
Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR, Iran
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 May 2010
Received in revised form
4 6
Application of a new catalytic system for cyanation reaction of various aryl halides using K [Fe(CN) ] as
cyanating source was examined. The reactions were performed under microwave irradiation and results
ꢀ
showed that application of this catalytic system and DMF at 130 C minimized the reaction times from
30 September 2010
hours to minutes in good to excellent yields.
Accepted 1 October 2010
Available online 30 October 2010
Ó 2010 Published by Elsevier B.V.
Keywords:
Cyanation reaction
K
4
[Fe(CN)
Catalyst
Palladium
6
]
1. Introduction
presence of free cyanide ion in the solution causes deactivation of
the catalyst [22]; therefore, employing this weakly ionizable source
As aryl nitriles can be used in both laboratory and industrial
scales [1] for the synthesis of various commercial components
including: agrochemicals, pharmaceuticals, dyes, pigments, herbi-
cides, natural products and so on [2e5], development of new
synthetic methods for cyanation of aryl halides and aryl triflates is
attractive subject in organic synthesis. Also CN group is equal to
functional groups such as carboxylic acids and their derivatives,
aldehydes, amines, amidines, thiazoles, triazoles, tetrazoles, oxa-
diazoles, etc., and can be applied for preparation of these functional
groups [2,3,6].
[23] has more advantages over the other cynation reagents [22,24].
In continuation of our previous work [25], we wish to report the
application of a new phosphine-based catalytic system for cyanation
reaction of different aryl halides under both conventional heating
and microwave irradiation. The reactions were performed with
reasonable reaction times and straightforward reaction conditions.
Thiscatalyst is homogeneousandtherefore canbe dissolved easilyin
reaction media causing all catalytic sites accessible to reactants in
solution [26,27].
Benzonitriles were synthesized by the addition of stoichio-
metric amount of CuCN as cyanating agent to aryl halides (Sand-
meyer reaction and Rosenmundevon Braun reaction) [7], however
this copper mediated reaction has required harsh conditions such
2
. Results and discussion
6 4 2 2 3
Palladacycle complex [Pd(C H CH NH - MOBPPY]
k2-C-N)PPh
OTf, (1) as catalyst was prepared according to our previous work
Scheme 1) [25] and its application as catalyst for the cyanation
ꢀ
as elevated temperature, sometimes more than 150 C [8]. More-
(
over, workup of the reaction mixture for removing of Cu salts from
reaction mixture is also harsh [9]. Other toxic cyanating sources
also were used [10e15]. Therefore, researches for finding the new
reaction of various types of aryl halides was examined. Initially to
optimize the reaction conditions, the reactions were performed
under both traditional and microwave irradiation conditions
and more safe reagents were performed recently, and K
4 6
[Fe(CN) ]
(
Table 1).
The cyanation of iodobenzene was tried for optimizing of the
reaction conditions in the presence of different bases in a solution
was chosen as a secure source for cynation [16e21]. Since the
*
Corresponding author. Pharmaceutical Research Laboratory, Department of
of DMF as solvent, palladacycle 1 as catalyst and K
cyanating reagent under microwave irradiation at 130 C. As
demonstrated in Table 1, K CO as the base gave the best yields.
2 3
4
[Fe(CN)
6
] as
Chemistry, Isfahan University of Technology, Isfahan 84156, IR, Iran.
Tel.: þ98 311 391 3262; fax: þ98 311 391 2350.
ꢀ
E-mail address: haji@cc.iut.ac.ir (A.R. Hajipour).
0
022-328X/$ e see front matter Ó 2010 Published by Elsevier B.V.
doi:10.1016/j.jorganchem.2010.10.002

820
A.R. Hajipour et al. / Journal of Organometallic Chemistry 696 (2011) 819e824
Table 2
Optimization of catalyst concentration in cyanation reaction of iodobenzene with
[Fe(CN) ] using palladacycle 1 under microwave irradiation.
K
4
6
a
Entry
Mol% cat.
Time (min)
Conversion (%)
1
2
3
4
5
6
None
0.01
0.1
0.5
1
4
4
4
4
4
4
0
20
55
90
90
95
2.5
a
Determined by GC.
and 3-bromoacetophenone as hindered substituted aryl halides. The
reaction of 2-bromoacetophenone performed slowly and full
conversion was not achieved (entry 6, Table 3), 3-bromoacetophe-
none as less bulker reacted more quicker than its 2-substituted
isomer, but again full conversion was not achieved (entry 7, Table 3).
Then the effect of chemoselectivity of the method was investigated
using 1-bromo-3-chlorobenzene as the test substrate. The reaction
performedquantitativelyandalsoshowedexcellentchemoselectivity
and only Brasa betterleaving group was substituted withcyanide ion
Scheme 1. The synthesis route for preparation of palladacycle complex 1.
Then, we applied several organic solvents under the same
reaction conditions by employing 0.5 mol% of palladacycle 1. The
data clearly showed that the best results were obtained using
microwave-active polar solvents such as N,N-dimethylformamide
DMF), N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide
DMSO), and the best solvent was DMF (Table 1).
(entry 12, Table 3 and entry 4, Table 4). Attempt to cyanation of 2-
(
(
bromopyridineassubstratewasnotsuccessful(entry14,Table 3).Aryl
cyanation reactions were also carried out using either electron-
releasing or electron-withdrawing groups on benzene rings and
found that these groups did not show any significant effect on the
yields and reaction times.
We also optimized the concentration of catalyst by employing
various amounts of catalyst for the reaction of iodobenzene and
[Fe(CN) ] in the presence of K CO as base in DMF as solvent. The
best results were obtained using 0.5 mol% of palladacycle 1 (Table
). Moreover, as each mol of K [Fe(CN) ] contains six-fold cyanide
ions, the ratio of K [Fe(CN) ] to aryl halide was chosen 0.2:1.
K
4
6
2
3
2
4
6
3. Experimental
4
6
These optimized reaction conditions were used for cyanation of
a vast range of aryl halides in the presence of this catalytic system
under both traditional and microwave irradiation conditions and
the results are summarized in Tables 3 and 4. As our catalyst was
oxygen insensitive therefore, all of the reactions were carried out
under air atmosphere.
As is shown in Tables 3 and 4, this catalyst can be used for cyan-
ation of aryl iodides, bromides and even less reactive aryl chlorides.
However, aryl chlorides were cyanated more slowly in comparison to
the iodides and bromides derivatives. The steric hindrance effect on
the yield and reaction times of the products was examined using 2-
3
.1. General
All melting points were taken on a Gallenkamp melting appa-
1
ratus and are uncorrected. H NMR spectra were recorded using
4
3
00 MHz in CDCl solutions at room temperature (TMS was used as
an internal standard) on a Bruker, Avance 500 instrument (Rhein-
stetten, Germany) and Varian 400 NMR. FT-IR spectra were recor-
ded on a spectrophotometer (Jasco-680, Japan). Spectra of solids
were carried out using KBr pellets. Vibrational transition frequen-
cies are reported in wave number (cm ). We used a Milestone
Microwave (Microwave Labstation-MLS GmbH-ATC-FO 300) for
synthesis. Also we used GC (BEIFIN 3420 Gas Chromatograph
equipped a Varian CP SIL 5CB column-30 m 0.32 mm 0.25 mm) for
examination of reaction completion and yields. All chemicals were
purchased from Merck and Aldrich and were used as received.
ꢁ1
Table 1
Optimization of base and solvent in cyanation reaction of iodobenzene with K
4
[Fe
(
CN) ] using palladacycle 1 under microwave irradiation.
6
2
NH -k
2-C-N)
3.2. Synthesis of palladacycle complex [Pd(C
6
H
4
CH
2
PPh MOBPPY]OTf (1)
3
[
Pd(C
6
H
4
CH
2
NH
2
-
k2-C-N)PPh
3
MOBPPY]OTf as
a
palladacycle
a
complex was prepared according to our previous work [25]. MOBPPY
Entry
Solvent
Base
Cs CO
CO
KOH
Time (min)
Conversion (%)
was prepared according to the Ramirez and Dershowitz method in two
1
2
3
4
5
6
DMF
DMF
DMF
Toluene
NMP
2
3
4
4
4
4
4
4
80
90
0
K
2
3
steps [28]. Interaction of 2-bromo-4 -methoxyacetophenone and PPh
3
25
Trace
85
gives the phosphonium salts, which then reacts with a weak base in
O to produce MOBPPY as a stable ylide which is not sensitive to air
2
K CO
2
K CO
2
K CO
3
3
3
H
2
and moisture.
Methanol
20
Then a freshly prepared solution of [Pd(C
6
H
4
CH
2
NH
2
-
k2-C-N)
3 2
PPh (Cl)]TfO reacts with MOBPPY (1:1 M ratio) in THF or Me CO at
a
Determined by GC.

A.R. Hajipour et al. / Journal of Organometallic Chemistry 696 (2011) 819e824
821
Table 3
Cyanation reaction of various aryl halides using K
4
[Fe(CN)
6
] in the presence of palladacycle 1 under microwave irradiation.a
Entry
1
ArX
Product
Time (min)
Yield (%)b
2
95
91
2
3
6
12
90
92
4
5
7
6
92
6
7
8
30
22
5
45
81
95
(
continued on next page)

822
A.R. Hajipour et al. / Journal of Organometallic Chemistry 696 (2011) 819e824
Table 3 (continued )
Entry
ArX
Product
Time (min)
Yield (%)b
9
15
72
1
1
0
1
11
12
85
76
12
13
14
3
4
91
91
20
Trace
1
1
5
6
13
20
91
73
a
ꢀ
4 6 2 2 3
[Fe(CN) ]$3H O; 0.22 mmol, K CO ; 2 mmol, palladacycle 1; 0.005 mmol, DMF; 4 ml, temperature; 130 C.
Reaction condition: aryl halide; 1 mmol, K
Isolated yield.
b
ꢀ
k2-C-N)
0
C and after 30 min stirring a white solid [Pd(C
6
H
4
CH
2
2
NH -
0.005 mmol of palladacycle 1 in DMF (4 ml) were added and heated
at 130 C under air atmosphere. In the case of microwave assisted
ꢀ
PPh
3
(MOBPPY)]OTf (1) was precipitated in good yields.
reactions the mixture was irradiated under microwave oven at
ꢀ
3.3. General procedure for the cyanation reaction of aryl halides
130 C and 600 W (using stirring magnetic bar). The mixture was
with K [Fe(CN)
4
6
]
stirred under these reaction conditions and reaction progress
was followed by GC. After completion of the reaction, the mixture
was cooled to room temperature and diluted with ether and water.
Organic layer was washed with brine, dried over MgSO4, filtered
and evaporated under reduced pressure using rotary evaporator to
In a round bottom flask equipped with a condenser for refluxing
and a stirring magnetic bar, K CO (2 mmol), aryl halide (1 mmol),
potassium hexacyanoferrate (II) (0.22 mmol) in the presence of
2
3

A.R. Hajipour et al. / Journal of Organometallic Chemistry 696 (2011) 819e824
823
Table 4
4 6
Cyanation reaction of various aryl halides using K [Fe(CN)
] in the presence of palladacycle 1 under heating conditions using an oil Bath.a
Entry
1
ArX
Product
Time (h)
1.5
Yield (%)b
90
88
86
2
3
5
4
4
5
3.25
92
85
4.5
6
7.5
82
7
8
5
87
90
3.75
(
continued on next page)

824
A.R. Hajipour et al. / Journal of Organometallic Chemistry 696 (2011) 819e824
Table 4 (continued )
Entry
9
ArX
Product
Time (h)
3.25
Yield (%)b
82
a
ꢀ
Reaction condition: aryl halide; 1 mmol, K
Isolated yield.
4
[Fe(CN)
6
]$3H
2
O; 0.22 mmol, K
2
CO
3
; 2 mmol, palladacycle 1; 0.005 mmol, DMF; 4 ml, temperature; 130 C.
b
give the crude product. The residue was purified by recrystalliza-
References
tion using ethanol and water.
[
[
[
1] B. Jiang, Y. Kan, A. Zhang, Tetrahedron 57 (2001) 158.
2] R.C. Larock, Comprehensive Organic Transformations. VCH, New York, 1989.
3] Z. Rappoport, Chemistry of the Cyano Group, first ed. John Wiley & Sons,
London, 1970.
3
.3.1. 4-Acetylbenzonitrile (entry 5, Table 3)
M.p. 57e58 C [29]; found 59e60 C. H NMR (400 MHz)
ꢀ
ꢀ
1
d: 8.06
[
4] (a) D.E. Uehling, S.S. Nanthakumar, D. Croom, D.L. Emerson, P.P. Leitner,
M.J. Luzzio, G. McIntyre, B. Morton, S. Profeta, J. Sisco, D.D. Sternbach,
W.Q. Tong, A. Vuong, J.M. Besterman, J. Med. Chem. 38 (1995) 1106;
(
d, 2H, J ¼ 8.0 Hz), 7.79 (d, 2H, J ¼ 8.4 Hz), 2.38 (s, 3H) ppm. IR (KBr,
ꢁ
1
cm ):
n 2225, 1690.
(b) S. Nagamura, E. Kobayashi, K. Gomi, H. Saito, Bioorg. Med. Chem. 4 (1996)
1
379.
3
.3.2. 4-Methoxybenzonitrile (entry 3, Table 3)
M.p. 59e60 C [29]; found 59e61 C; H NMR (400 MHz)
ꢀ
ꢀ
1
[5] A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances:
Syntheses, Patents, Applications, fourth ed. Georg Thieme, Stuttgart, 2001.
[6] R.C. Larock, Comprehensive Organic Transformations. Wiley-VCH, New York,
1988.
d
:
:
13
7.57e7.60 (m, 2H), 6.94e6.97 (m, 2H), 3.86 (s, 3H); C NMR
d
ꢁ
1
163.5, 134.8 (2C), 128.1, 115.0 (2C), 114.7, 56.2 ppm. IR (KBr, cm ): n
[
7] (a) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 17 (1884) 1633;
2
221.
(
(
b) H.H. Hodgson, Chem. Rev. 40 (1947) 251;
c) C. Galli, Chem. Rev. 88 (1988) 765;
3
.3.3. 3-Chlorobenzonitrile (entry 12, Table 3)
M.p. 136e140 C [30]; found 137e140 C; H NMR (400 MHz)
(d) E.B. Merkushev, Synthesis (1988) 923;
(e) R. Bohlmann, in: B.M. Trost, I. Fleming (Eds.), Comprehensive Organic
Synthesis, 6, Pergamon, Oxford, 1991, p. 203;
ꢀ
ꢀ
1
d:
7
(
.95e7.97 (m, 1H), 7.90e7.93 (m, 1H), 7.60e7.65 (m, 1H), 7.55e7.58
(
f) K.W. Rosenmund, E. Struck, Ber. Dtsch. Chem. Ges. 2 (1919) 1749;
(g) J. Lindley, Tetrahedron 40 (1984) 1433.
[8] G.A. Ellis, T.M. Romney-Alexander, Chem. Rev. 87 (1987) 779.
9] P.E. Maligres, M.S. Waters, F. Fleitz, D. Askin, Tetrahedron Lett. 40 (1999) 8193.
m, 1H) ppm. 13C NMR
d
: 136.5, 136.0, 132.3, 130.9, 117.8, 117.9 and
ꢁ
1
102.5 ppm. IR (KBr, cm ):
n
2218.
[
[
10] D.M. Tschaen, R. Desmond, A.O. King, M.C. Fortin, B. Pipik, S. King,
3
.3.4. Phenantrene-9-carbonitrile (entry 9, Table 3)
T.R. Verhoeven, Synth. Commun. 24 (1994) 887.
ꢀ
ꢀ
1
[11] T. Okano, J. Kiji, Y. Toyooka, Chem. Lett. (1998) 425.
M.p. 88e92 C [30]; found 90e92 C. H NMR (400 MHz)
t, 2H, J ¼ 8.4 Hz), 8.30 (d, 1H, J ¼ 8.4 Hz), 8.26 (s, 1H), 7.95 (d, 1H,
J ¼ 8 Hz), 7.78e7.84 (m, 3H), 7.72 (t, 1H, J ¼ 7.6 Hz) ppm. IR (KBr,
d: 8.70
[
[
12] F. Jin, P.N. Confalone, Tetrahedron Lett. 41 (2000) 3271.
13] B.A. Anderson, E.C. Bell, F.O. Ginah, N.K. Harn, L.M. Pagh, J.P. Wepsiec, J. Org.
Chem 63 (1998) 8224.
(
ꢁ
1
[
[
14] A.J. Allentoff, B. Markus, T. Duelfer, A. Wu, L. Jones, G. Ciszewska, T. Ray,
J. Labelled Compd. Radiopharm. 43 (2000) 1075.
15] T. Sakamono, K. Ohsawa, J. Chem. Soc., Perkin Trans. 1 (1999) 2323.
cm ):
n 2224.
4
. Conclusion
[16] T. Schareina, A. Zapf, M. Beller, Chem Commun. (2004) 1388.
[
[
[
17] C. DeBlase, N.E. Leadbeater, Tetrahedron 66 (2010) 1098.
18] S. Velmathi, N.E. Leadbeater, Tetrahedron Lett. 49 (2008) 4693.
19] T. Schareina, A. Zapf, W. Mägerlein, N. Müller, M. Beller, Tetrahedron Lett. 48
We have successfully synthesized a new palladium-based
catalyst and applied this novel catalyst for the cyanation reaction of
aryl halides using K [Fe(CN) ] as the safe cyanating agent under
both conventional heating and microwave irradiation. The results
were compared and showed that in comparison to traditional
heating conditions, reaction times under microwave irradiation can
be reduced from hours to minutes.
(2007) 1087.
[20] N.S. Nandurkar, B.M. Bhanage, Tetrahedron 64 (2008) 3655.
4
6
[
[
21] A. Schareina, A. Zapf, M. Beller, J. Organomet. Chem 689 (2004) 4576.
22] S. Erhardt, V.V. Grushin, A.H. Kilpatrick, S.A. Macgregor, W.J. Marshall,
D.C. Roe, J. Am. Chem. Soc. 130 (2008) 4828.
[23] M. Sundermeier, A. Zapf, M. Beller, Eur. J. Inorg. Chem. (2003) 3513.
[
24] (a) K.D. Dobbs, W.J. Marshall, V.V. Grushin, J. Am. Chem. Soc. 129 (2007) 30.
b) M. Sundermeier, A. Zapf, M. Beller, Angew. Chem., Int. Ed. 42 (2003) 1661.
25] K. Karami, Transition Met. Chem. 33 (2008) 819.
(
[
Acknowledgment
[26] J. Hagen, Industrial Catalysis: A Practical Approach. Wiley-VCH, Weinheim,
999.
1
[
[
27] D.J. Cole-Hamilton, Science 299 (2003) 1702.
28] F. Ramirez, S. Dershowitz, J. Org. Chem. 22 (1957) 41.
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran.
Further financial supportfrom CenterofExcellence inSensorResearch
[29] M. Hatsuda, M. Seki, Tetrahedron 61 (2005) 9908.
30] A.R. Hajipour, K. Karami, A. Pirisedigh, Appl. Organometal. Chem. 24 (2010)
54.
[
4
(IUT) is gratefully acknowledged.