Pd/C: A recyclable catalyst for cyanation of aryl bromides

Article abstract of DOI:10.1002/ejoc.200700098

Aryl cyanides have been prepared from the corresponding aryl bromides with potassium hexacyanoferrate(II) using Pd/C as a catalyst. It is shown that the addition of Bu₃N is the key factor in obtaining the corresponding aryl cyanides. Furthermore, the catalyst can be recycled by filtration and washing sequences, making the method also attractive for industrial applications. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700098

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700098
Pd/C: A Recyclable Catalyst for Cyanation of Aryl Bromides
Yi-Zhong Zhu[a] and Chun Cai*[a]
Keywords: Cyanation / Heterogeneous catalysis / Potassium hexacyanoferrate(II) / Palladium / Aryl cyanides
Aryl cyanides have been prepared from the corresponding
aryl bromides with potassium hexacyanoferrate(II) using
Pd/C as a catalyst. It is shown that the addition of Bu3N is
the key factor in obtaining the corresponding aryl cyanides.
Furthermore, the catalyst can be recycled by filtration and
washing sequences, making the method also attractive for
industrial applications.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
dust + 20 mol-% Br2) is active for cyanation of aryl bro-
mides.[4j,4k] However, its success remained linked to the use
Introduction
Aryl cyanides are of considerable interest as integral part of PPh3 as ligand.
of dyes, herbicides, natural products and pharmaceuticals.[1]
Quite recently, we chose to investigate a heterogeneous
In addition, cyanides play a crucial role as they can be eas- Pd/C (5 wt.-%) catalyst in the cyanation of aryl halides. The
ily converted into a variety of functional groups such as reason for using Pd/C is the prospect of attaining much
acids, ketones, oximes and amines.[2]
cleaner reactions as palladium can be removed by simple
Various methods for the synthesis of aryl cyanides have filtration. The “Pd/C” catalyst system for cyanation of aryl
been reported. One of the most convenient methods is bromides using potassium hexacyanoferrate(II)[7] as cya-
based on the transition-metal-mediated displacement of nide source would also be of major interest for both indus-
aromatic halides by the cyanide ion. Since the discovery of trial and academic applications.
transition-metal-catalyzed cross-coupling reactions, much
interest has been devoted to the development of a practical
version of this transformation.[3] Until now, a number of
successful palladium- and nickel-catalyzed protocols have
been reported.[4,5] However, most of the work has concen-
trated on the inconvenient traditional cyanide sources
which have some severe drawbacks. In order to avoid these
problems, potassium hexacyanoferrate(II) was rediscovered
as a non-toxic cyanide source by Beller.[4f] However, potas-
sium hexacyanoferrate(II) as a cyanide source was only
used in homogeneous catalyst system.[4f,4h,4m,4p,4r] Until
now, the existing methods employing homogeneous Pd cat-
alyst still suffer from at least one of two drawbacks: quite
expensive and hazardous phosphane ligands were generally
needed,[4f,4p,4r] recycling of the catalyst was tedious. A good
way to overcome these problems would be the use of sup-
ported catalysts that are extensively studied for Heck and
Suzuki reactions.[6] Nevertheless, only few reports described
the cyanation catalyzed by heterogeneous Pd catalysts.[4j,4k]
Seki and co-workers have shown that the heterogeneous
system (4 mol-% Pd/C + 16 mol-% PPh3 + 40 mol-% Zn
Results and Discussion
As a starting point for the development of our cyanation
system, the reaction of bromobenzene with K4[Fe(CN)6]
was investigated. The results are recorded in Table 1. At
first the reaction of bromobenzene in the presence of 1 mol-
% Pd/C (5 wt.-%), 20 mol-% dry K4[Fe(CN)6] and 100 mol-
% Na2CO3 in N,N-dimethylacetamide (DMAc) at 140 °C
for 21 h resulted in poor conversion (Table 1, Entry 1). In-
creasing the amount of Pd/C only led to a slightly increase
in product yield (Table 1, Entries 2, 3). Encouraged by some
successful reports of one-pot domino halogen exchange
(Halex) coupling reactions,[3b,8] we also tried using this
method but found that this had a deleterious effect on the
reaction (Table 1, Entry 4).
Since tetrabutylammonium salts have been reported to
increase the efficiency by stabilizing palladium nanopar-
ticles,[9] the yield, however, of the desired product decreased
when performing the reaction in the presence of phase-
transfer catalysts (Table 1, Entries 5, 6).
Then some co-catalysts widely successfully used in coup-
ling reactions to reduce high-valent transition-metal ions to
their corresponding low-valent ones, such as Zn,[10]
HCOONa,[11] and iPrOH,[12] were explored. It was found
that the use of Zn as a co-catalyst did not facilitate the
[a] Chemical Engineering College, Nanjing University of Science &
Technology,
Nanjing 210094, China
Fax: +86-25-8431-5030
E-mail: c.cai@mail.njust.edu.cn
Eur. J. Org. Chem. 2007, 2401–2404
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2401

Y.-Z. Zhu, C. Cai
SHORT COMMUNICATION
Table 1. Evaluation of various reaction conditions.[a]
Table 2. Cyanation of bromobenzene in the presence of different
amines.[a]
Entry
Pd/C (mol- Additive (mol-
Conv.
(%)
Yield (%)
Amine (mol-%)[b]
Conv. (%)
Yield (%)[c]
[b]
%)
%)
Entry
1
2
3
4
5
6
7
8
9
1
3
5
3
3
3
1
1
1
1
1
1
1
1
1
–
–
–
40
42
43
30
13
12
43
85
60
Ͼ 99
92
Ͼ 99
19
Ͼ 99
Ͼ 99
37
38
39
1
2
3
4
5
6
1,10-phen (50)
bipy (50)
-proline (50)
TMEDA (50)
Et3N (50)
15
19
44
56
94
93
7
16
32
10
78
85
KI (300)
TBAB (50)
PEG-400 (50)
Zn (50)
HCOONa (50)
iPrOH (50)
–
Bu3N (50)
Bu3N (50)
Bu3N (50)
Bu3N (50)
Bu3N (50)
27
Ͻ 2
Ͻ 2
26
15
54
50
82
87
17
DABCO (50)
[a] 3.0 mmol bromobenzene, 1 mol-% Pd/C (5 wt.-%), 20 mol-%
dry K4[Fe(CN)6], 5 mL NMP, 100 mol-% Na2CO3, under N2,
140 °C, 24 h. [b] DABCO = 1,4-diazabicyclo[2.2.2]octane, 1,10-
phen = 1,10-phenanthroline, bipy = 2,2Ј-bipyridine, TMEDA =
N,N,NЈ,NЈ-tetramethylethylenediamine. [c] Yields were determined
by GC with 1,3-dimethoxybenzene as the internal standard.
10[c]
11
12[d]
13[e]
14[d,f]
15[d,g]
91
81
[a] Reaction conditions: 3.0 mmol bromobenzene, 1–5 mol-% Pd/
C (5 wt.-%), 20 mol-% dry K4[Fe(CN)6], 5 mL solvent, 100 mol-%
Na2CO3, under N2, 140 °C, 21 h. [b] Yields were determined by
GC with 1,3-dimethoxybenzene as the internal standard. [c] Under
H2. [d] Reaction time 24 h. [e] No Na2CO3. [f] Solvent: NMP.
[g] Solvent: DMF.
example, CH3CO, F, NO2, CF3, CHO for the cyanation.
They led to the products in good to excellent yields
(Table 3, Entries 1–7). Aryl bromides with electron-donat-
ing groups, such as methyl and methoxy, exhibited some-
what diminished yields of the corresponding products and
lower selectivity due to the formation of biaryls at pro-
longed reaction times (Table 3, Entries 9–11). However, the
substrate with an amino group was not compatible with the
reaction conditions (Table 3, Entry 12). This suggested that
the oxidative addition of aryl halide to the Pd catalyst could
be the rate-determining step in the reaction. We also at-
tempted to extend the suggested method to a more inexpen-
sive aryl chloride such as 4-chlorobenzotrifluoride. Unfor-
tunately, the corresponding cyanide was obtained in a very
low yield (4%) accompanied by a large amount of biaryl
(Table 3, Entry 13).
reaction (Table 1, Entry 7). HCOONa gave good conver-
sion but lower yield due to dehalogenation (Table 1, En-
try 8). Only a slight increase in product yield was observed
when iPrOH was used (Table 1, Entry 9). When performing
the reaction under H2 excellent conversion could be
achieved, but large amounts of dehalogenation product
were also obtained (Table 1, Entry 10).
Fortunately, the reactivity of the catalyst system was
greatly enhanced in the presence of Bu3N (Table 1, En-
try 11). The synthesis of benzonitrile in an excellent conver-
sion and with a good yield (Table 1, Entry 12) was achieved
by an increase of the reaction time. A blank test using Bu3N
as base without Na2CO3 afforded benzonitrile only in a
poor yield of 17% (Table 1, Entry 13). Addition of Bu3N
was essential to run the reaction effectively and suggested
that Bu3N might play an important role in stabilizing the
catalyst in the catalytic cycle. Thus, the combination of
Na2CO3 with Bu3N plays a key role in improving the cata-
lytic activity.
Table 3. Pd/C-catalyzed cyanation of various aryl halides.[a]
Entry
Ar-X
Ar-CN Time (h) Conv. (%) Yield (%)[b]
The use of other solvents such as NMP, DMF all
brought about good yields, and NMP gave the best result
(Table 1, Entries 14, 15).
1
2
3
4
5
6
7
8
9[c]
10[d]
11[d]
12[d]
13[d]
β-bromonaphthalene
p-CH3COC6H4Br
p-FC6H4Br
p-O2NC6H4Br
p-CF3C6H4Br
m-CF3C6H4Br
m-CHOC6H4Br
C6H5Br
p-CH3C6H4Br
p-CH3OC6H4Br
o-CH3OC6H4Br
p-H2NC6H4Br
p-CF3C6H4Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
2
2
2
2
100
100
100
Ͼ 99
Ͼ 99
Ͼ 99
100
Ͼ 99
91
95
92
94
88
89
87
88
91
80
50
40
–
The beneficial effect of Bu3N as additive prompted us to
examine other amines in the cyanation of bromobenzene.
The results are shown in Table 2. Interestingly, the presence
of 1,10-phen, bipy, -proline or TMEDA inhibited rather
than facilitated the reaction (Table 2, Entries 1–4). Et3N
and DABCO promoted this reaction effectively; neverthe-
less, they were less effective than Bu3N (Table 2, Entries 5,
6).
To evaluate the scope and limitations of this procedure,
the reactions of a wide variety of aryl halides were exam-
ined (Table 3). Very efficient transformation of an array of
commercially available β-bromonaphthalene and aryl bro-
2
2
24
36
36
36
36
36
2j
2k
2l
Ͼ 99
95
–
2m
63
4
[a] Reaction conditions: 3.0 mmol aryl halide, 20 mol-% dry
K4[Fe(CN)6], 1 mol-% Pd/C (5 wt.-%), 5 mL NMP, 100 mol-%
Na2CO3, 50 mol-% Bu3N, under N2, 140 °C. [b] Yields were deter-
mined by GC with 1,3-dimethoxybenzene as the internal standard.
mides bearing a variety of electron-withdrawing groups, for [c] 2 mol-% Pd/C was used. [d] 3 mol-% Pd/C was used.
2402 Eur. J. Org. Chem. 2007, 2401–2404
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Pd/C: A Recyclable Catalyst for Cyanation of Aryl Bromides
SHORT COMMUNICATION
with water (2ϫ15 mL) and 5% NH4OH (1ϫ15 mL). The organic
phase was dried with Na2SO4, filtered, and concentrated in vacuo.
The crude product obtained was purified by silica gel chromatog-
raphy with hexane and ethyl acetate as eluent. All prepared benzo-
nitriles are known compounds and identified by GC-MS.
In order to illustrate the recycling of the catalyst, 4-bro-
mobenzotrifluoride was cyanated under Pd/C, with Bu3N
as additive, NMP as solvent and Na2CO3 as base. After
filtering off the product, Pd/C was washed with deionized
water and CH2Cl2, and dried in air at room temperature.
The dried catalyst was then reused directly in the next reac-
tion. The same procedure was repeated for all further cycles.
In addition, the amount of palladium of the crude product
was determined by ICP-AES. The Pd content was found to
be 0.45 ppm. On the other hand, the Pd content for using
the same, but homogeneous catalyst system [0.1 mol-%
Pd(OAc)2] was 1.76 ppm which is higher than that for the
Pd/C catalyst system. This catalytic system has the advan-
tages of homogeneous catalysis to some extent. Although,
the catalytic activity was gradually diminished, the yield
was still 80% even in the third reuse (Table 4). Therefore, it
is easy for the catalyst to be reused, and it has a potential
application on an industrial scale.
[1]
a) K. C. Liu, R. K. Howe, J. Org. Chem. 1983, 48, 4590–4592;
b) T. M. Harris, C. M. Harris, T. A. Oster, L. E. Brown Jr,
J. Y. C. Lee, J. Am. Chem. Soc. 1988, 110, 6180–6186.
[2]
[3]
R. C. Labrock, Comprehensive Organic Transformations, VCH,
New York, 1989, pp. 819–995.
a) M. Sundermeier, A. Zapf, S. Mutyala, W. Baumann, J. San,
S. Weiss, M. Beller, Chem. Eur. J. 2003, 9, 1828–1836; b) J.
Zanon, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003,
125, 2890–2891.
[4]
For palladium-catalyzed cyanation of aryl halides, see:a) M.
Sundermeier, A. Zapf, M. Beller, Eur. J. Inorg. Chem. 2003,
3513–3526 and references cited therein; b) A. Zhang, J. L.
Neumeyer, Org. Lett. 2003, 5, 201–203; c) R. Chidambaram,
Tetrahedron Lett. 2004, 45, 1441–1444; d) K. M. Marcantonio,
L. F. Frey, Y. Liu, Y. Chen, J. Strine, B. Phenix, D. J. Wallace,
C. Y. Chen, Org. Lett. 2004, 6, 3723–3725; e) S. E. Collibee,
R. R. Strivastava, Tetrahedron Lett. 2004, 45, 8895–8897; f) T.
Schareina, A. Zapf, M. Beller, Chem. Commun. 2004, 1388–
1389; g) J. M. Williams, C. Y. Yang, Org. Lett. 2004, 6, 2837–
2840; h) T. Schareina, A. Zapf, M. Beller, J. Organomet. Chem.
2004, 689, 4576–4583; i) F. Stazi, G. Palmisano, M. Turconi,
M. Stantagostino, Tetrahedron Lett. 2005, 46, 1815–1818; j) M.
Hatsuda, M. Seki, Tetrahedron 2005, 61, 9908–9917; k) M.
Hatsuda, M. Seki, Tetrahedron Lett. 2005, 46, 1849–1853; l)
M. L. Jensen, A. S. Gajare, K. Toyota, M. Yoshijuji, F. Ozawa,
Tetrahedron Lett. 2005, 46, 8645–8647; m) S. A. Weissman, D.
Zewge, C. Chen, J. Org. Chem. 2005, 70, 1508–1510; n) L. S.
Lin, B. P. Fors, H. R. Chobanian, Tetrahedron Lett. 2006, 47,
3303–3305; o) J. Whittall, P. M. Cormack, W. R. Pitts, Tetrahe-
dron 2006, 62, 4705–4708; p) D. Gelman, O. Grossman, Org.
Lett. 2006, 8, 1189–1191; q) L.-H. Li, Z.-L. Pan, Y.-M. Liang,
Synlett 2006, 2094–2098; r) T. Schareina, A. Zapf, W. Magerl-
ein, N. Muller, M. Beller, Tetrahedron Lett. 2007, 48, 1087–
1090.
Table 4. Recycling of the catalyst (without addition of fresh cata-
lyst).[a]
Entry
Pd/C
Yield (%)[b]
1
2
3
4
fresh
88
87
84
80
first reuse
second reuse
third reuse
[a] Reaction conditions: 3.0 mmol p-CF3C6H4Br, 20 mol-% dry
K4[Fe(CN)6], 5 mL NMP, 100 mol-% Na2CO3, 50 mol-% Bu3N,
140 °C, 2 h. 1 mol-% Pd/C (5 wt.-%) was used in the first run, then
the recovered catalyst was used directly in the next runs. [b] Yields
were determined by GC with 1,3-dimethoxybenzene as the internal
standard.
Conclusions
[5]
For nickel-catalyzed cyanation of aryl halides, see:a) L. Cassar,
J. Organomet. Chem. 1973, 54, 57–58; b) L. Cassar, M. Foà, F.
Montanari, G. P. Marinelli, J. Organomet. Chem. 1979, 173,
335–339; c) Y. Sakaibara, F. Okuda, A. Shimoyabashi, K. Kir-
ino, M. Sakai, N. Uchino, K. Takagi, Bull. Chem. Soc. Jpn.
1988, 61, 1985–1990; d) Y. Sakaibara, F. Okuda, A. Shimoyab-
ashi, Y. Ido, K. Sakai, M. Sakai, N. Uchino, Bull. Chem. Soc.
Jpn. 1993, 66, 2776–2778; e) V. Percec, J.-Y. Bae, D. H. Hill, J.
Org. Chem. 1995, 60, 6895–6903; f) N. E. Leadbeater, R. K.
Arvela, J. Org. Chem. 2003, 68, 9122–9125.
We propose a Pd/C-catalyzed method for the cyanation
of aryl bromides using potassium hexacyanoferrate(II)
which is non-toxic and inexpensive. This protocol avoids the
use of expensive and/or air-sensitive ligands. High catalytic
activity was obtained using Na2CO3 with Bu3N. A variety
of aryl halides gave the corresponding benzonitriles in good
to excellent yields. Furthermore, Pd/C can be recycled by
simple filtration and washing sequences, even in the third
reuse.
[6]
a) L. Djakovith, K. Koehler, J. Am. Chem. Soc. 2001, 123,
5990–5999; b) S. S. Prockl, K. M. Wolfgang, A. Gruber, K.
Koehler, Angew. Chem. Int. Ed. 2004, 43, 1881–1882; c) M. S.
McClure, F. Roschangar, S. J. Hodson, A. Millar, M. H. Oster-
hout, Synthesis 2001, 1681–1685; d) C. R. LeBond, A. T. And-
rews, Y. Sun, J. R. Sowa Jr, Org. Lett. 2001, 3, 1555–1557; e)
H. Sakurai, T. Tsukuda, T. Hirao, J. Org. Chem. 2002, 67,
2721–2722; f) R. G. Heidenreich, K. Kohler, J. G. E. Krauter,
J. Pietsch, Synlett 2002, 1118–1122; g) M. G. Organ, S. Mayer,
J. Comb. Chem. 2003, 5, 118–124; h) A. Arcadi, G. Cerichelli,
M. Chiarini, M. Correa, D. Zorzan, Eur. J. Org. Chem. 2003,
4080–4086; i) J. Horniakova, T. Raja, Y. Kubota, Y. Sugi, J.
Mol. Catal. A 2004, 217, 73–80; j) A. Papp, K. Millos, M.
Forgo, A. Molnar, J. Mol. Catal. A 2005, 229, 107–116; k) A.
Molnar, A. Papp, Synlett 2006, 3130–3134; l) Z.-H. Zhang, Z.-
Y. Wang, J. Org. Chem. 2006, 71, 7485–7487.
Experimental Section
General Procedure for the Cyanation of Aryl Halides: After stan-
dard cycles of evacuation and filling with dry and pure nitrogen,
an oven-dried tube was charged with aryl halide (3 mmol),
K4[Fe(CN)6] (221 mg, 20 mol-%), Pd/C (5 wt.-%, 64 mg, 1 mol-%),
Bu3N (278 mg, 50 mol-%), Na2CO3 (318 mg, 3 mmol), and NMP
(5 mL). The tube was evacuated and filled with nitrogen. Then the
tube was sealed and the mixture was stirred at 140 °C for 24 h.
After cooling to room temperature, the mixture was diluted with
ethyl acetate (30 mL) and filtered. Then 1,3-dimethoxybenzene
(800 µL) was added as the internal standard and the mixture was
analyzed by GC. For isolating the products, the filtrate was washed
[7]
K4[Fe(CN)6]·3H2O is ground to a fine powder and dried under
a high vacuum at 80 °C overnight.
Eur. J. Org. Chem. 2007, 2401–2404
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2403

Y.-Z. Zhu, C. Cai
[11] P. Bamfield, P. M. Quan, Synthesis 1978, 537–538.
[12] J. Hassan, V. Penalva, L. Lavenot, C. Gozzi, M. Lemaire, Tet-
rahedron 1998, 54, 13793–13804.
SHORT COMMUNICATION
[8] a) G. Rothenberg, M. B. Thathagar, Org. Biomol. Chem. 2006,
4, 111–115; b) H.-J. Cristau, A. Ouali, J.-F. Spindler, M.
Taillefer, Chem. Eur. J. 2005, 11, 2483–2492.
[9] M. T. Reetz, J. G. de Vries, Chem. Commun. 2004, 1559.
[10] a) S. Venkatraman, C. J. Li, Org. Lett. 1999, 1, 1133–1135; b)
S. Mukhopadhyay, G. Rothenberg, D. Gitis, Y. Sasson, Org.
Lett. 2000, 2, 211–214.
Received: February 6, 2007
Published Online: April 4, 2007
2404
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2401–2404