A new palladium catalyst system for the cyanation of aryl chlorides with K4[Fe(CN)6]

Article abstract of DOI:10.1016/j.tetlet.2006.12.087

The development of a novel Pd-catalyzed synthesis of (hetero)aromatic nitriles from the corresponding aryl chlorides and potassium hexacyanoferrate(II) is described. This novel protocol avoids the use of highly toxic alkali cyanides and proceeds in the presence of small amounts of palladium catalysts. High yields and selectivities of the corresponding aryl nitriles were achieved applying di(1-adamantyl)-1-butylphosphine (cataCXium A) as the ligand.

Full text of DOI:10.1016/j.tetlet.2006.12.087

Tetrahedron Letters 48 (2007) 1087–1090
A new palladium catalyst system for the cyanation
of aryl chlorides with K [Fe(CN) ]
4
6
a
a
b
Thomas Schareina, Alexander Zapf, Wolfgang M a¨ gerlein,
b
a,
*
Nikolaus M u¨ ller and Matthias Beller
a
Leibniz-Institut f u¨ r Katalyse e.V. an der Universit a¨ t Rostock, Albert-Einstein-Str. 29A, 18059 Rostock, Germany
b
Saltigo GmbH, Building Q 18-2, 51369 Leverkusen, Germany
Received 1 December 2006; accepted 13 December 2006
Abstract—The development of a novel Pd-catalyzed synthesis of (hetero)aromatic nitriles from the corresponding aryl chlorides and
potassium hexacyanoferrate(II) is described. This novel protocol avoids the use of highly toxic alkali cyanides and proceeds in the
presence of small amounts of palladium catalysts. High yields and selectivities of the corresponding aryl nitriles were achieved apply-
Ò
ing di(1-adamantyl)-1-butylphosphine (cataCXium A) as the ligand.
Ó 2006 Elsevier Ltd. All rights reserved.
Aromatic nitriles are of considerable importance in
organic chemistry as integral part of dyes, herbicides,
natural products and pharmaceuticals. Classical methods
nickel catalysts (up to 10 mol %) has been reported pre-
1
0
viously. Palladium catalysts are in general more toler-
ant towards a variety of functional groups compared to
nickel catalysts, and in addition can be more easily
tuned for activating aryl–Cl bonds. Thus, there still ex-
ists a considerable interest in developing palladium cat-
1
for the preparation of benzonitriles involve the Rosen-
mund–von Braun reaction of aryl halides and stoichio-
2
metric amounts of copper(I) cyanide, diazotization
3
6
of anilines and subsequent Sandmeyer reaction, and
alysts for this reaction. The cyanation of aryl chlorides
4
on an industrial scale the ammoxidation reaction. Since
via palladium catalysis has been observed only recently,
except in the case of strongly activated C–Cl bonds. The
first more general procedure was reported by Jin and
Confalone who discovered that aryl chlorides react with
zinc(II) cyanide in the presence of catalytic amounts of
the mid 70s the synthesis of aryl nitriles via transition
metal-catalyzed cyanation of aryl halides using inexpen-
sive cyanide salts such as potassium cyanide or sodium
5
–7
cyanide has become more popular.
0
Pd (dba) , 1,1 -bis(diphenylphosphino)ferrocene (dppf)
2
3
1
1
In order to fully exploit the synthetic potential of this
reaction it is important that all kinds of aryl and hetero-
aryl halides can be used as starting materials for this
transformation. From an environmental point of view
and zinc to give the corresponding nitriles. A draw-
back of this procedure is the use of overstoichiometric
amounts (1.2 equiv) of expensive and toxic zinc(II) cya-
nide, which leads to the formation of large amounts of
zinc(II) waste. Additional disadvantages of this proce-
dure are the use of 4 mol % palladium catalyst and
the need of zinc as an additive (12 mol %). A newer pro-
8
and for applications in the fine chemical industry the
efficient activation of inexpensive and readily available
9
aryl bromides and chlorides instead of aryl iodides is
1
2
desirable. In general, the C–Cl bond in aryl chlorides
is more difficult to activate than C–Br or C–I bonds.
Nevertheless, the cyanation of aryl chlorides with either
potassium cyanide or sodium cyanide in the presence of
various additives and comparatively large amounts of
cedure makes use of microwave activation in the pres-
ence of 2 mol % palladium and SPhos as the ligand.
Again, zinc(II) cyanide is used as cyanide source here.
So far the most efficient Pd-catalyzed cyanation of chlo-
roarenes has been described by us dosing acetone cyano-
1
3
hydrin in a controlled manner in the reaction mixture.
More recently, we were able to demonstrate that in the
cyanation of aryl bromides highly toxic cyanides can
be replaced by potassium hexacyanoferrate(II), which
*
Corresponding author. Tel.: +49 381 1281 0; fax: +49 381 1281
000; e-mail addresses: matthias.beller@cataylsis.de; matthias.
beller@ifok-rostock.de
5
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.087

1088
T. Schareina et al. / Tetrahedron Letters 48 (2007) 1087–1090
is essentially the least toxic cyanide source conceivable.
While all known other cyanation sources, for example,
KCN (LDLo (oral, human) = 2.86 mg/kg), are highly
poisonous, K [Fe(CN) ] is more or less non-toxic (the
toxic K [Fe(CN) ] in the presence of less than 1 mol %
4 6
of commercially available palladium catalysts.
The cyanation of 2-chlorotoluene served as a model
reaction in order to study the influence of temperature,
Pd content, and ligands (Fig. 1; Table 1). Due to its elec-
tronic and steric nature, 2-chlorotoluene is a more diffi-
cult to activate substrate. According to our previous
work a high-boiling polar solvent, temperatures of at
least 140 °C and dried potassium hexacyanoferrate(II)
were used. As expected exploratory reactions in the pres-
ence of aryl phosphines (e.g., PPh , P(o-tolyl) ) gave no
4
6
LD50 of K [Fe(CN) ] is lower than that for NaCl).
4
6
Our new approach has proven its initial value in both
1
4
15
palladium- and copper-catalyzed cyanations of aryl
bromides and has been adopted nicely by other
groups.
1
6
In this Letter we report a new procedure for the direct
cyanation of aryl chlorides using inexpensive and non-
3
3
desired 2-methylbenzonitrile. Also carbene ligands,
which have proven to form highly active electron rich
palladium catalysts for a multitude of similar reac-
1
7
tions, showed no activity under these conditions.
Therefore we focused on the use of strongly basic and
sterically hindered phosphine ligands (Fig. 1). As shown
in Table 1 only in the presence of ligand 1 (di(1-adaman-
P
P
Ò
tyl)-1-butylphosphine; cataCXium A) yields of more
than 50% are observed. The superiority of this ligand
for aryl–X activation reactions has already been shown
in the formylation of aryl- and heteroaryl bromides.
1
2
1
8
Cy
The second best ligand is tri-tert-butyl phosphine (2;
P
PCy2
O
P
Table 1, entries 5 and 6), while a series of so-called
O
Cy
1
9
Buchwald’s ligands (ligands 4–7) provided yields in
the range of 30–50% and below. An interesting feature
of the model reaction is the fact that the best result with
ligand 1 is obtained with the potassium hexacyano-
ferrate(II) trihydrate (Table 1, entry 1).
3
4
5
Cy
P
Cy
Cy
P
This is in contrast to our previous experiments with aryl
bromides as starting materials, where no cyanation reac-
tion took place in the presence of crystal water. How-
ever, other groups have not observed a detrimental
effect of a water content of 60 mol % in the reaction ves-
Cy
6
7
16a
sel. The direct addition of water to a system with dry
K [Fe(CN) ], under otherwise the same conditions, led
Figure 1. Tested ligands.
4
6
a
Table 1. Palladium-catalyzed cyanation of 2-chlorotoluene
Pd catalyst
PR3
Cl
CN
+
K [Fe(CN) ]
4 6
NMP
40-160 ºC; 16 h
1
b
b
Entry Solvent Temperature (°C) Pd precursor (mol % Pd) Na
2
CO
3
Ligand (mol %)
K
4
[Fe(CN)
6
]
Conversion
(%)
Yield
(%)
Selec.
(%)
(
mol %)
1
2
3
4
5
6
7
8
9
0
1
NMP
NMP
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
140
140
140
140
140
160
160
140
160
160
160
Pd(OAc)
2
(0.33)
20
—
20
20
20
5
1 (1)
1 (1)
1 (1)
1 (1)
2 (1)
2*HBF
3*HBF
4 (0.75)
5 (1)
6 (1)
Hydrate
Hydrate
Dried
Dried
Dried
Dried
Dried
Dried
Dried
Dried
Dried
100
97
87
21
54
16
20
24
45
16
13
99
97
78
19
47
9
99
>99
90
88
86
52
40
95
69
Pd
2
Pd
2
Pd
2
dba
dba
dba
3
3
3
(0.33)
(0.33)
(0.33)
(0.5)
(0.5)
(0.5)
(0.25)
(0.5)
(0.5)
(0.5)
c
Pd(OAc)
2
Pd
Pd
2
dba
dba
3
4
4
(1)
(1)
2
3
5
9
Pd(OAc)
2
20
10
—
—
22
32
4
Pd
2
Pd
2
Pd
2
dba
dba
dba
3
3
3
1
1
24
12
7 (1)
1
a
General reaction conditions: 2 mmol 2-chlorotoluene, 0.4 mmol K
4 6
[Fe(CN) ], metal precursor and ligand in stock solution in the given solvent,
filled up to 2 ml, 200 ll internal standard (tetradecane), 16 h at temperature given, in a pressure tube under argon.
Conversions and yields were determined by GC, average of 2 experiments.
b
c
50 ll water were added.

T. Schareina et al. / Tetrahedron Letters 48 (2007) 1087–1090
1089
to a reduced yield of the product (Table 1, entry 4).
Obviously, there is no significant difference between
Pd(II)- and Pd(0)-pre-catalysts (Table 1, entries 1 and 2).
benzonitrile with as little as 0.33 mol % palladium
in 87% yield (Table 2, entry 5). It is well-known that pal-
ladium-catalyzed cyanations with sterically hindered
substrates are much more difficult to perform. Accord-
ingly, mono-ortho-substituted chloroarenes such as 1-
chloro-2-(trifluoromethyl)benzene and o-chlorotoluene
resulted in yields of 82% and 99%, respectively (Table
2, entries 2 and 4).
After realization of the successful cyanation of 2-chloro-
toluene, we were interested in exploring the scope and
2
0
limitations of this new protocol. Hence, a number of
different chloroarenes were reacted under standard con-
ditions. It turned out that the conditions, which have
been optimized for 2-chlorotoluene, were not fully satis-
factory for other substrates. Especially the use of potas-
sium hexacyanoferrate(II) trihydrate is preferable only
for one more starting material, 1-chloro-2-(trifluoro-
methyl)benzene (Table 2, entry 2). In all other cases an
improved yield is obtained under water-free conditions.
Notably, applying catalyst loadings below 0.1 mol % Pd
resulted in less reproducible experiments.
As an example for an electron-poor nitrogen heterocycle
3-chloropyridine was cyanated in 88% yield (Table 2,
entry 9).
In summary, we have developed a general protocol for
the palladium-catalyzed cyanation of electron-rich and
-poor aryl chlorides utilizing non-toxic potassium hexa-
cyanoferrate(II) as the cyanide source. This procedure is
complementary to our previous protocols applying aryl
bromides. Noteworthy, the cyanation proceeds in a high
yield and selectivity using catalyst amounts of
0.2–0.5 mol %. Further applications of this chemistry
towards the use of Cu catalysts are under way in our
laboratory.
As shown in Table 2 both activated and non-activated
aryl chlorides gave the desired benzonitriles in good to
excellent yields, although with a slight variation of the
catalyst amount. Remarkably, the sterically hindered
2
-chloro-1,3-dimethylbenzene yielded 2,6-dimethyl-
a
Table 2. Scope and limitations of the palladium-catalyzed cyanation of aryl and heteroaryl chlorides
Pd(OAc) /1
2
Cl
+
K4[Fe(CN)6]
NC
R
16 h
R
b
b
Entry
1
Substrate
Solvent
NMP
T (°C)
Pd(OAc)
2
(mol %)
K
4
[Fe(CN)
6
]
Conversion (%)
Yield (%)
Selectivity (%)
80
Cl
140
0.25
Dried
94
75
Cl
2
3
4
5
DMAc
NMP
NMP
NMP
160
160
140
160
0.25
0.5
Hydrate
Dried
85
99
82
74
99
91
97
74
99
95
F3C
Cl
Cl
CF3
0.33
0.5
Hydrate
Dried
100
96
Cl
Cl
Cl
6
7
NMP
NMP
140
160
0.33
0.5
Dried
89
92
87
73
97
79
Dried
Dried
8
9
Cl
Cl
OCH3
NMP
NMP
160
160
0.5
0.5
83
82
88
98
88
Dried
100
N
a
General conditions: 2 mmol aryl or heteroaryl chloride, 0.4 mmol Na
2
3 4 6
CO , 0.4 mmol K [Fe(CN) ], metal precursor and ligand 1 (P:Pd = 3:1) in
stock solution in the given solvent, filled up to 2 ml, 200 ll internal standard (tetradecane), 16 h at temperature given, in a pressure tube under
argon.
b
Conversions and yields were determined by GC, average of 2 experiments.

1090
T. Schareina et al. / Tetrahedron Letters 48 (2007) 1087–1090
Acknowledgements
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other cyanations of aryl chlorides see: (b) Sundermeier,
M.; Zapf, A.; Beller, M.; Sans, J. Tetrahedron Lett. 2001,
The authors thank Dr. W. Baumann, Dr. C. Fischer,
Mrs. S. Buchholz, Mrs. S. Schareina and Ms. K. Rein-
cke for analytical assistance. Generous financial support
from the state Mecklenburg-Vorpommern, the BMBF,
the Deutsche Forschungsgemeinschaft (Leibniz price),
and Saltigo GmbH are gratefully acknowledged.
4
2, 6707; (c) Sundermeier, M.; Zapf, A.; Mutyala, S.;
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1
2
Organomet. Chem. 2004, 689, 4576.
5. Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005,
46, 2585.
1
1
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2
3
. Lindley, J. Tetrahedron 1984, 40, 1433.
(
b) Herrmann, W. A. Angew. Chem. 2002, 114, 1342;
. For a recent catalytic variant of the Sandmeyer reaction
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Chem. 2006, 118, 161; Angew. Chem., Int. Ed. 2006, 45,
4
1
54; for some other applications of this ligand in coupling
reactions see: (b) Michalik, D.; Kumar, K.; Zapf, A.;
Tillack, A.; Arlt, M.; Heinrich, T.; Beller, M. Tetrahedron
Lett. 2004, 45, 2057; (c) Tewari, A.; Hein, M.; Zapf, A.;
Beller, M. Synthesis 2004, 935; (d) Datta, A.; Ebert, K.;
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Plenio, H. Chem. Commun. 2003, 1504; (f) Benedi, C.;
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M. Angew. Chem. 2000, 112, 4315; Zapf, A.; Ehrentraut,
A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153;
5
6
. For the palladium-catalyzed cyanation of aryl bromides
and iodides see: (a) Anderson, B. A.; Bell, E. C.; Ginah, F.
O.; Harn, N. K.; Pagh, L. M.; Wepsiec, J. P. J. Org. Chem.
1
998, 63, 8224; (b) Anderson, Y.; L a˚ ngstr o¨ m, B. J. Chem.
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Takagi, K.; Okamoto, T.; Sakakibara, Y.; Ohno, A.; Oka,
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Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Chem.
Lett. 1973, 471.
(
j) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000,
589.
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1
1
2
1
570; Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
999, 38, 2413; (b) Fox, J. M.; Huang, X. H.; Chieffi, A.;
7
. For the copper-catalyzed cyanation of aryl halides see: (a)
Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2005, 11, 2483; (b) Zanon, J.; Klapars, A.;
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8
9
Am. Chem. Soc. 2003, 125, 11818; (e) Milne, J. E.;
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2
0. Standard reaction procedure: Potassium hexacyanofer-
*
rate(II) (0.4 mmol) (either powdered K
or dry [Fe(CN)
[Fe(CN)
ca. 2 mbar) at 80 °C overnight), 2 mmol aryl chloride,
.4 mmol Na CO , metal precursor and ligand (in a stock
4
[Fe(CN)
6
] 3H
2
O
K
4
6
], which is yielded by grinding
] 3H O to a fine powder and drying in vacuum
*
K
(
0
4
6 2
2
3
solution in the given solvent) are mixed in a pressure tube
under argon. Then the solvent (filled up to 2 ml) and
1
0. (a) Rock, M.-H.; Merhold, A. WO Patent 98/37058, 1998;
b) Sakakibara, Y.; Ido, Y.; Sasaki, K.; Sakai, M.;
2
00 ll of internal standard (tetradecane) are added and the
(
mixture is stirred for 16 h at the given temperature. After
cooling to room temperature, 3 ml of dichloromethane are
added and the reaction mixture is analyzed by GC.
Conversion and yield are calculated as average of 2
parallel runs. The products can be isolated by column
chromatography (SiO , ethyl acetate/hexane) after wash-
2
ing the organic phase with water, drying over sodium
sulfate and distilling the solvents.
Uchino, N. Bull. Chem. Soc. Jpn. 1993, 66, 2776; (c)
Sakakibara, Y.; Okuda, F.; Shimoyabashi, A.; Kirino, K.;
Sakai, M.; Uchino, N.; Takagi, K. Bull. Chem. Soc. Jpn.
1
988, 61, 1985; (d) Cassar, L.; Fo a` , M.; Montanari, F.;
Marinelli, G. P. J. Organomet. Chem. 1979, 173, 335.
1. Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
2. Chobanian, H. R.; Fors, B. P.; Lin, L. S. Tetrahedron Lett.
1
1
2006, 47, 3303.