A new palladium catalyst system for the cyanation of aryl chlorides

Article abstract of DOI:10.1016/S0040-4039(01)01390-9

The influence of reaction conditions and additives on the palladium-catalyzed cyanation of aryl chlorides with potassium cyanide has been investigated. Successful cyanation of aryl chlorides is observed in the presence of palladium catalysts using potassium cyanide. It is shown that the combination of a 1,5-bis(diphenylphosphino)pentane ligand and the addition of N,N,N′,N′-tetramethylethylenediamine (TMEDA) as a co-catalyst are the key factors in obtaining the corresponding aryl nitriles with improved catalyst productivities and selectivities.

Full text of DOI:10.1016/S0040-4039(01)01390-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6707–6710
A new palladium catalyst system for the cyanation of
†
aryl chlorides
a
a
a,
b
Mark Sundermeier, Alexander Zapf, Matthias Beller * and J u¨ rgen Sans
a
Institut f u¨ r Organische Katalyseforschung an der Universit a¨ t Rostock e.V. (IfOK), Buchbinderstraße 5–6,
D-18055 Rostock, Germany
b
Degussa AG, Werk Trostberg, Dr.-Albert-Frank-Straße 32, D-83303 Trostberg, Germany
Received 12 June 2001; accepted 27 July 2001
Abstract—The influence of reaction conditions and additives on the palladium-catalyzed cyanation of aryl chlorides with
potassium cyanide has been investigated. Successful cyanation of aryl chlorides is observed in the presence of palladium catalysts
using potassium cyanide. It is shown that the combination of a 1,5-bis(diphenylphosphino)pentane ligand and the addition of
N,N,N%,N%-tetramethylethylenediamine (TMEDA) as a co-catalyst are the key factors in obtaining the corresponding aryl nitriles
with improved catalyst productivities and selectivities. © 2001 Elsevier Science Ltd. All rights reserved.
Aryl nitriles are of considerable importance in organic
chemistry as integral parts of dyes, herbicides, natural
products and pharmaceuticals. In general, aryl nitriles
are synthesized from aryl halides and stoichiometric
amounts of copper(I) cyanide (Rosenmund–von Braun
reaction), from aniline via diazotization and a subse-
quent Sandmeyer reaction, or on an industrial scale via
ammoxidation. Alternatively, aryl nitriles may be syn-
thesized by the transition metal-catalyzed cyanation of
aryl halides using inexpensive cyanide salts such as
tion of aryl chlorides via palladium catalysis has not
been observed until very recently, except in the case of
strongly activated CꢀCl bonds. A more general proce-
dure was reported last year by Jin and Confalone who
discovered that aryl chlorides react with zinc(II) cya-
nide in the presence of catalytic amounts of Pd (dba) ,
2
3
1,1%-bis(diphenylphosphino)ferrocene (dppf) and zinc to
5
give the corresponding nitriles. A drawback of this
procedure is the use of overstoichiometric amounts (1.2
equiv.) of expensive zinc(II) cyanide, which leads to the
formation of stoichiometric amounts of zinc(II) chlo-
ride waste. Additional disadvantages of these proce-
dures are the use of 4 mol% palladium-catalyst and the
need of zinc as an additive (12 mol%).
1–3
potassium cyanide or sodium cyanide.
In order to
make this reaction attractive for the fine chemical
industry it is important to be able to use inexpensive
4
and readily available aryl chlorides instead of aryl
iodides or bromides. Unfortunately, the CꢀCl bond in
aryl chlorides is much more difficult to activate than
In this paper we report the first procedure for the direct
cyanation of activated aryl chlorides using inexpensive
potassium cyanide in the presence of catalytic amounts of
palladium catalysts. The cyanation of 4-chloroben-
zotrifluoride with potassium cyanide served initially as
a model reaction in order to study the influence of
critical reaction parameters (solvent, temperature, con-
centration of starting materials), ligands, and co-cata-
lysts (Fig. 1, Table 1).
1a
CꢀBr or CꢀI bonds. In the past comparatively large
amounts of nickel catalysts (0.8–10 mol%) were
reported to catalyze the cyanation of aryl chlorides with
either potassium cyanide or sodium cyanide in the
2
presence of various additives. Palladium catalysts are
in general more tolerant than nickel catalysts towards a
variety of functional groups and in addition can be
more easily tuned for activating arylꢀX bonds. There is
thus a considerable interest in developing palladium
3
6
catalysts for this reaction. Unfortunately, the cyana-
In agreement with results from the patent literature we
observed a low conversion for the model reaction to
give 38% of 4-cyanobenzotrifluoride at 160°C in the
presence of 2 mol% Pd(OAc) /PPh3 and a catalytic
*
Corresponding author. Tel.: +49-381-46693-0; fax: +49-381-46693-
4; e-mail: matthias.beller@ifok.uni-rostock.de
Palladium-catalyzed reactions for fine chemical synthesis, Part 21;
2
amount of a crown ether and base (Table 1, entry 1).
As side product ca. 4% benzonitrile is formed due to
2
†
7
for Part 20, see: Zapf, A.; Beller, M. Chem. Eur. J. 2001, 7, 2908.
aryl-aryl-scrambling between the aryl chloride and the
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01390-9

6
708
M. Sundermeier et al. / Tetrahedron Letters 42 (2001) 6707–6710
Pd catalyst
PR3
Cl
CF3
+ KCN
NC
CF3
toluene
1
40-160 °C, 16 h
Figure 1. Pd-catalyzed cyanation of 4-chlorobenzotrifluoride.
a
Table 1. Pd-catalyzed cyanation of 4-chlorobenzotrifluoride
Entry
Na CO3 (mol%)
18-Crown-6 (mol%)
TMEDAb (mol%)
Ligand
Conversion (%)c
Yield (%)c
2
1
2
3
4
5
6
7
8
9
20
20
20
20
0
20
20
0
0
0
0
0
2
2
1
4
0
2
0
2
0
0
0
0
0
0
0
0
0
0
0
0
20
20
20
20
20
20
20
20
20
20
PPh3
42
63
50
50
15
56
28
10
97
10
1
38
58
41
43
13
49
23
8
91
7
0
4
2
d
d
d
d
d
d
d
Dpppe
Dpppe
Dpppe
Dpppe
Dpppe
Dpppe
Dpppe
Dpppe
PPh3
PCy3
d
10
11
12
13
14
15
e
Dppp
Dppb
Dpph
4
3
46
23
f
0
0
0
g
42
7
Dppfh
a
General conditions: 2 mmol 4-chlorobenzotrifluoride, 2 mmol potassium cyanide, 0.04 mmol palladium(II) acetate, molar ratio Pd:P=1:4, 2 ml
toluene, 16 h, 160°C, in a pressure tube.
b
c
d
e
f
N,N,N%,N%-Tetramethylethylenediamine.
Conversions and yields were determined by GC using an internal standard (diethyleneglycol di-n-butylether).
1
1
1
,5-Bis(diphenylphosphino)pentane.
,3-Bis(diphenylphosphino)propane.
,4-Bis(diphenylphosphino)butane.
g
h
1
1
,6-Bis(diphenylphosphino)hexane.
,1%-Bis(diphenylphosphino)ferrocene.
phenyl groups of the phosphine. Hence, we thought the
use of sterically more hindered ligands such as tri-o-
tolylphosphine and tricyclohexylphosphine should
improve the catalyst stability. Unfortunately, no better
results were obtained in the presence of these and
similar ligands. Variation of other phosphines revealed
a significant improvement by using chelating ligands.
Best yields were obtained in the presence of chelating
phosphines forming seven or eight-membered chelate
rings. Among the various phosphine ligands tested in
the model reaction 1,5-bis(diphenylphosphino)pentane8
gave best yields of 4-cyanobenzotrifluoride (58%)
under the described conditions (Table 1, entry 2).
other hand the exchange of cyanide with other ligands
is facilitated.
9
Next we considered using organic bases as co-catalysts.
Especially chelating amines should also influence the
solubility and ligand exchange reactions of cyanide with
palladium. Unfortunately, different combinations of
TMEDA with sodium carbonate and 18-crown-6
resulted in significantly lower yields of the desired
product as shown in Table 1 (entries 6–8). However, the
addition of 0.2 equiv. of N,N,N%,N%-tetramethyl-
ethylenediamine (TMEDA) alone led to a conversion of
97% and a yield of 91% of 4-cyano-benzotrifluoride
(
Table 1, entry 9).
Since it is known that the concentration of cyanide ions
in solution strongly influences the outcome of the palla-
dium-catalyzed cyanation of aryl bromides, we tested
different concentrations of 18-crown-6, which enable
the solubility of the cyanide ions to be controlled
Among the various ligands tested in the presence of the
TMEDA co-catalyst, only 1,5-bis(diphenylphosphino)-
pentane and 1,6-bis(diphenylphosphino)hexane showed
significant conversion. In agreement with our initial
ligand study the use of dpppe as the ligand gives the
best yields of the corresponding aryl nitrile (Table 1,
entries 9–15).
(
Table 1, entries 2–5). The best results were obtained by
applying sodium carbonate, 18-crown-6 and the palla-
dium catalyst in a molar ratio of 10:1:1 (58% of 4-
cyanobenzotrifluoride). Without any base or crown
ether added the desired product is obtained in only 13%
yield. From a mechanistic standpoint the positive influ-
ence of base and crown ether is twofold: on the one
hand the concentration of cyanide is controlled, on the
After realization of the successful cyanation of 4-
chlorobenzotrifluoride we were interested in exploring
the scope and limitations of this new protocol. As
shown in Table 2 activated aryl chlorides (methyl 4-
1
0

M. Sundermeier et al. / Tetrahedron Letters 42 (2001) 6707–6710
6709
a
Table 2. Scope and limitations of the Pd-catalyzed cyanation of aryl and heteroaryl chlorides
chlorobenzoate, 2-chlorobenzonitrile, 4-chloroace-
tophenone) yield the corresponding nitriles in good to
excellent yields (75–96%) and very good selectivities.
Non-activated aryl chlorides (chlorobenzene and 3-
chlorotoluene) give the desired products in lower yields
Crucial to the success of the reaction is the use of
catalytic amounts of TMEDA. It is clear that despite
the development of the reported procedure for the
practical application further improvements have to be
made (reduction of catalyst amount; increasing catalyst
activity). Nevertheless the unexplored potential of the
new co-catalysts makes us confident that the use of
other chelating bases will lead to even better catalyst
systems in future. Also, the combination of chelating
amines with palladium catalysts may improve catalyst
productivity (activity) for the cyanation of aryl
bromides.
(
17–33%), while N-heteroaryl chlorides provide the cor-
responding nitriles in moderate to good yields (46–
4%).
7
In summary, we have shown that the palladium-cata-
lyzed cyanation of activated aryl chlorides (Fig. 2) can
be performed using simple KCN as cyanide source. The
use of stoichiometric amounts of zinc or copper metal
or salts can be avoided. Therefore no stoichiometric
amounts of environmentally harmful transition metal
chlorides are formed during the reaction.
Acknowledgements
Financial support of this work by former SKW AG,
Degussa AG and the State Mecklenburg-Western
Pomerania is gratefully acknowledged. Mrs. S. Buch-
holz and Dr. C. Fischer (both IfOK) are thanked for
their excellent analytical service. Dr. S. Weiss (Degussa
AG) and Dr. M. Hateley (IfOK) is thanked for helpful
suggestions concerning this project.
Pd(OAc) /dpppe
TMEDA, KCN
2
Cl
NC
toluene
60 °C, 16 h
R
R
1
Figure 2. Pd-catalyzed cyanation of aryl chlorides.

6
710
M. Sundermeier et al. / Tetrahedron Letters 42 (2001) 6707–6710
Chem. 2000, 595, 186; (h) Littke, A. F.; Fu, G. C. J. Org.
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2
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