Progress in the palladium-catalyzed cyanation of aryl chlorides

Article abstract of DOI:10.1002/chem.200390210

The development of new palladium catalysts for the cyanation of various aryl and heteroaryl chlorides is described. The combination of amine co-catalysts with chelating phosphine ligands, for example, 1,4-bis(diphenylphosphino)butane (dppb) or 1,5-bis(diphenylphosphino)pentane (dpppe), allows an efficient cyanation of chloroarenes with simple potassium cyanide. General palladium-catalyzed cyanation of nonactivated and deactivated chloroarenes is possible for the first time. Studies of the oxidative addition of aryl halides to palladium triphenylphosphine complexes in the presence and absence of amines suggest that the co-catalyst is capable of preventing catalyst deactivation caused by the presence of excess cyanide ions in solution.

Full text of DOI:10.1002/chem.200390210

FULL PAPER
Progress in the Palladium-Catalyzed Cyanation of Aryl Chlorides
Mark Sundermeier,[a] Alexander Zapf,[a] Sateesh Mutyala,[a] Wolfgang Baumann,[a]
J¸rgen Sans,[b] Stefan Weiss,[b] and Matthias Beller*[a]
Abstract: The development of new palladium catalysts for the cyanation of various
aryl and heteroaryl chlorides is described. The combination of amine co-catalysts
with chelating phosphine ligands, for example, 1,4-bis(diphenylphosphino)butane
(dppb) or 1,5-bis(diphenylphosphino)pentane (dpppe), allows an efficient cyanation
Keywords: aryl chlorides ¥ benzoni-
of chloroarenes with simple potassium cyanide. General palladium-catalyzed
triles ¥ cyanation ¥ homogeneous
cyanation of nonactivated and deactivated chloroarenes is possible for the first time.
catalysis ¥ palladium
Studies of the oxidative addition of aryl halides to palladium triphenylphosphine
complexes in the presence and absence of amines suggest that the co-catalyst is
capable of preventing catalyst deactivation caused by the presence of excess cyanide
ions in solution.
high activity of these ligands with aryl chlorides as substrates
has been demonstrated in Suzuki[4] and Heck[5] reactions,
Introduction
Palladium-catalyzed coupling reactions of aryl halides have
attracted widespread interest for the synthesis of organic
building blocks and pharmaceutical and agrochemical deriv-
atives. In addition to small-scale applications (<1 to 100 g),
there is increasing awareness of the possible application of
this type of reaction for industrial fine chemical synthesis (1 to
>100 t per annum).[1] When availability is taken into account,
aryl chlorides are economically the most attractive starting
materials among the aryl halides. Some time ago, we started a
research program to develop palladium-catalyzed coupling
reactions of aryl chlorides to a practical level. Initially, the so-
called palladacycle was introduced by Herrmann et al. and us
as a stable and robust palladium complex.[2] This catalyst gives
high turnover numbers for Heck and Suzuki coupling
reactions of activated aryl chlorides. However, the catalyst
activity is not sufficient to allow an efficient activation of
neutral and electron-rich aryl chlorides. Hence, we and other
groups developed palladium catalysts based on sterically
hindered basic phosphines, which are more active and
productive.[3] We were the first to introduce alkyldiadaman-
tylphosphines as ligands for active palladium catalysts. The
palladium-catalyzed amination,[6] and arylation reactions of
ketones.[7] We also demonstrated that basic chelating phos-
phines based on the ferrocene core allow a general carbon-
ylation of nonactivated chloroarenes.[8] Carbene ligands, as
well as electron-rich phosphine ligands, have been demon-
strated to generate active palladium catalysts for aryl chloride
activation.[9]
Recently we became interested in the cyanation of aryl
chlorides also. This transformation offers a simple and elegant
approach towards substituted benzonitriles from a number of
available aryl and heteroaryl chlorides. The resulting benzo-
nitriles are of considerable industrial importance as integral
parts of dyes, herbicides, natural products, agrochemicals,
pharmaceuticals, and new active agents. A selection of drugs is
shown in Figure 1.[10]
In general, aryl cyanides are synthesized from aryl halides
and stoichiometric amounts of copper(i) cyanide (Rosen-
mund von Braun reaction), from aniline by diazotization and
subsequent Sandmeyer reaction, or on an industrial scale by
ammoxidation.[11] Alternatively, benzonitriles may be synthe-
sized by the transition-metal-catalyzed cyanation of aryl
halides using inexpensive cyanide salts such as potassium
cyanide or sodium cyanide.[12, 13]
[a] Prof. Dr. M. Beller, Dr. M. Sundermeier, Dr. A. Zapf,
Dr. S. Mutyala, Dr. W. Baumann
In the past, comparatively large amounts of nickel catalysts
(up to 10 mol%) were reported to catalyze the cyanation of
aryl chlorides with either potassium cyanide or sodium
cyanide in the presence of various additives. Apparently,
researchers from Bayer have recently improved this method:
the nickel-catalyzed cyanation of 4-chlorobenzotrifluoride on
a ton scale has been reported.[12d, 14]
Institut f¸r Organische Katalyseforschung
an der Universit‰t Rostock e.V.
Buchbinderstrasse 5 6, 18055 Rostock (Germany)
Fax : (‡49)3814669324
E-mail: matthias.beller@ifok.uni-rostock.de
[b] Dr. J. Sans, Dr. S. Weiss
Degussa AG, Werk Trostberg
Dr.-Albert-Frank-Strasse 32, 83303 Trostberg (Germany)
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1828 1836
F
CN
O
O
S
O
N
CF3
N
H
N
N
NC
HO
CH3
F
O
NC
Citalopram
Bicalutamid
Fadrozole
Cipramil (Promonta Lundbeck)
antidepressant, selective serotonin-
uptake inhibitor
Casodex (Zeneca)
Arensin (Ciba-Geigy)
antineoplastic, non-steroidal
aromatase inhibitor
non-steroidal antiandrogen,
antineoplastic, anti(prostate)cancer
NC
CN
O
N
N
N
CN
N
S
CN
N
N
S
N
Periciazine
Letrozole
Cyamemazine
Neutromil (Farmitalia)
neuroleptic, tranquilizer
Aolept (Bayer)
Femara (Novartis Pharma)
antipsychotic, neuroleptic
antineoplastic, aromatase inhibitor
Figure 1. Selected cyano-substituted pharmaceuticals.
Palladium catalysts are in general more tolerant towards a
variety of functional groups than nickel catalysts, and they can
be tuned more easily for activating aryl X bonds. Hence,
there is interest in developing improved palladium catalysts
for this reaction. The cyanation of aryl chlorides using
palladium catalysis was not observed until very recently,
nobenzotrifluoride in the presence of a combination of
Pd(OAc)2, 1,5-bis(diphenylphosphino)pentane (dpppe), and
N,N,N',N'-tetramethylethylenediamine (TMEDA) as organic
co-catalyst (Scheme 1). We have also shown that these
reaction conditions are useful for the cyanation of other
activated aryl and heteroaryl chlorides. Less activated or
sterically hindered aryl chlorides react only sluggishly under
these conditions.
À
except in the case of strongly activated C Cl bonds. The most
general procedure was reported in 2000 by Jin and Confalone,
who discovered that aryl chlorides react with zinc(ii) cyanide
in the presence of catalytic amounts of [Pd2(dba)3] (dba ˆ
trans,trans-dibenzylideneacetone), 1,1'-bis(diphenylphosphi-
no)ferrocene (dppf), and zinc to give the corresponding
nitriles.[15] A drawback of this procedure is the use of an
almost stoichiometric amount (0.6 equiv) of zinc(ii) cyanide,
which leads to the formation of heavy metal salt waste. Other
disadvantages of this procedure are the use of 4 mol%
palladium catalyst and the need for zinc as an additive
(12 mol%). More recently, we reported on the first procedure
for the direct cyanation of activated aryl chlorides using
inexpensive potassium cyanide in the presence of catalytic
amounts of palladium catalysts.[16] However, nonactivated aryl
chlorides such as chlorobenzene and 3-chlorotoluene gave the
corresponding nitriles in only low yields (17 33%). Here, we
present a full account of our work on catalyst development for
the cyanation of aryl chlorides, which has led to a significantly
improved procedure for the cyanation of activated, non-
activated and even deactivated aryl chlorides and heteroaryl
chlorides, and we offer new insight into the mechanism of the
palladium-catalyzed cyanation.
Pd(OAc)2, dpppe,
TMEDA
Cl
CF3
+ KCN
NC
CF3
toluene
140-160 °C; 16h
Scheme 1. Palladium-catalyzed cyanation of 4-chlorobenzotrifluoride.
Further studies of our model reaction revealed that the
reaction is sensitive to the amount of TMEDA present. As
shown in Table 1 (entries 1 4), at least 20 mol% of the amine
is necessary to obtain the desired product, 4-cyanobenzotri-
fluoride, in good yield. Next, we were interested in reducing
the amount of catalyst. Early results (Table 1, entries 5, 6)
showed that a simple decrease in the amount of palladium
complex leads to a breakdown of the catalytic activity. We
assumed that cyanide ions might inhibit the palladium catalyst
(see the discussion under Mechanistic Studies). If so, at a
constant catalyst concentration an increased amount of
starting material should be converted successfully, because
the ratio of catalyst to dissolved cyanide ions has not changed
(Table 1, entries 7 9). Indeed, it is possible to increase the
turnover number (TON) by a factor of 2, to approximately
100. However, a further increase is not possible due to the
insolubility of potassium cyanide and potassium chloride,
which results in a high loading of solids in the reaction
mixture.
Results and Discussion
Catalysis: In our preliminary communication we reported that
the cyanation of 4-chlorobenzotrifluoride proceeds with
excellent conversion (97%) and yield (91%) to give 4-cya-
Chem. Eur. J. 2003, 9, No. 8
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M. Beller et al.
FULL PAPER
Table 1. Pd-catalyzed cyanation of 4-chlorobenzotrifluoride.[a]
Entry
4-Chlorobenzo-
trifluoride [mmol]
Pd(OAc)2
[mol%]
TMEDA
[mol%]
Conversion[b]
[%]
Yield[b]
[%]
Selectivity
[%]
TON
1
2
3
4
5
6
7
2
2
2
2
2
2
4
8
20
2
2
2
2
1
1
1
0.5
0.2
10
20
30
40
20
10
20
20
20
26
97
94
94
3
24
91
88
85
0
92
94
92
91
0
32
90
90
1
12
46
44
43
0
2
1
1
77
57
10
70
49
0
70
98
0
8
9[c]
[a] General conditions: 4-chlorobenzotrifluoride, potassium cyanide (1 equiv), dpppe (Pd/P ˆ 1:4), toluene (2 mL), 16 h, 1608C, in a pressure tube.
[b] Conversions and yields were determined by GC using an internal standard (diethylene glycol di-n-butyl ether). [c] Magnetic stirring breaks down because
of the high solids loading.
The beneficial effect of TMEDA as co-catalyst prompted us
to investigate the influence of other amines in the palladium-
catalyzed cyanation of nonactivated chloroarenes. Here,
chlorobenzene is a more suitable model system which does
not react efficiently with KCN under standard conditions; for
example, benzonitrile is obtained in only 13% yield in the
presence of 0.2 equivalents of TMEDA and 2 mol% palla-
dium catalyst. All catalytic experiments using different co-
catalysts were performed in ACE pressure tubes with toluene
as solvent in the presence of 2 mol% Pd(OAc)2. To ensure
reproducibility, each run was performed at least twice. Where
observed yield differences were >10%, a third experiment
was carried out. In agreement with our previous optimization
study, a Pd/dpppe ratio of 1:2 was used. More than 25 primary,
secondary, and tertiary amines were tested as co-catalysts
(Table 2).
The reaction outcome is influenced significantly by the
added amine. Among the various amines tested, the best
results were achieved in the presence of 0.2 equivalents of
sparteine (Table 2, entry 5: 62% benzonitrile), 1,1'-methyl-
enedipiperidine (Table 2, entry 7: 66%), 2,2'-bipyridine
(Table 2, entry 10: 64%), and 1-adamantylamine (Table 2,
entry 13: 60%). In the case of 1-adamantylamine a slight
increase in the yield of benzonitrile (Table 2, entry 14: 66%)
was observed when the amount of additive was reduced to 0.1
equivalents. Interestingly, no palladium-catalyzed amination
(Buchwald Hartwig reaction) was observed in this case.
There is no clear trend regarding the product yield and the
basicity or steric hindrance of the amine.
enes to determine the scope and limitations of this new
protocol. To compare the new co-catalyst appropriately with
the previous catalyst system, reactions were also performed in
the presence of TMEDA (Table 4).
Apart from chlorobenzene, we tested 4-chlorotoluene,
3-chloroanisole, and 5-chloroindole as non- or deactivated
aryl chlorides. 4-Chlorobenzaldehyde, 2,4-difluorochloroben-
zene, and 4-chloro-2-nitrotoluene were used as activated
chloroarenes. Activated but sterically more hindered aryl
chlorides such as 2-chlorobenzotrifluoride and methyl 2-chlor-
obenzoate were also employed. We also used 3-chloropyr-
idine, 4-chloroquinaldine, and 2-chloro-6-methoxypyridine as
interesting heteroaryl chlorides. Except for 5-chloroindole,
the corresponding aryl cyanides were obtained in moderate to
excellent yields by using reaction conditions optimized for
chlorobenzene and 4-chlorobenzotrifluoride. In general, the
use of 0.2 equivalents of MDP as the organic co-catalyst led to
significantly improved yields of the corresponding nitriles,
compared with the use of TMEDA. Somewhat surprisingly, in
the cases of 3-chloroanisole (Table 4, entries 7, 8) and
4-chloroquinaldine (Table 4, entries 20, 21) we observed
better results using TMEDA.
Interestingly, the palladium-catalyzed cyanation of 4-chlor-
obenzaldehyde with KCN gives 4-cyanobenzaldehyde in very
good yield (86%) (Table 4, entry 1). In general, cyanide-
catalyzed benzoin condensation would be expected to occur
in this case. However, the free cyanide ions should be trapped
by the palladium; hence, catalytic cyanation is preferred to the
classic benzoin condensation. 4-Chloro-2-nitrotoluene (Ta-
ble 4, entries 9 11) was used as substrate, because the
corresponding 4-methyl-3-nitrobenzonitrile and 4-cyanoben-
zaldehyde represent intermediates in the synthesis of hydroxy-
stilbamide, a potent antiprotozoal agent.[10, 17] Unfortunately,
the corresponding nitrile was obtained only in a moderate
yield (55%). Remarkably, the cyanation of nonactivated,
deactivated, and sterically hindered aryl chlorides proceeded
smoothly. 4-Chlorotoluene, 3-chloroanisole, and chloroben-
zene (Table 4, entries 2 8) gave the desired nitriles in good
yields (59, 82, and 84%, respectively). 5-Chloroindole reacted
with KCN in low yields (22%) under our reaction conditions.
Sterically hindered aryl chlorides such as 2-chlorobenzotri-
fluoride (Table 4, entries 16, 17) and methyl 2-chlorobenzoate
(Table 4, entries 18, 19) gave the corresponding nitrile in
sufficient yield (73 75%). The use of TMEDA as addi-
As we had better co-catalysts to hand, we also tested the
cyanation of chlorobenzene in the presence of phosphines
other than dpppe (Table 3). Monodentate basic phosphines,
which give good results in other types of coupling reactions,
do not catalyze the reaction appreciably. However, the use of
1,4-bis(diphenylphosphino)butane (dppb) leads to some im-
provement and gives 89% conversion and 84% yield of
benzonitrile. To our knowledge, this is the first efficient
palladium-catalyzed cyanation of a nonactivated aryl chloride
with simple alkali cyanide to be reported. Furthermore, when
the variation of the Pd:P ratio was tested again under our new
conditions, as expected the best results were obtained with
Pd:P ˆ 1/4, as in the case of TMEDA.
Next, we tested 1,1'-methylenedipiperidine (MDP) in the
presence of Pd(OAc)2/2dpppe or dppb with other chloroar-
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Pd-Catalyzed Cyanation of Aryl Chlorides
1828 1836
Table 2. Catalytic cyanation of chlorobenzene in the presence of different
co-catalysts.[a]
Table 3. Catalytic cyanation of chlorobenzene in the presence of different
phosphines.[a]
Entry Amine
Amine
Conversion[b] Yield[b]
Entry
Ligand
Conversion[b] [%]
Yield[b] [%]
concentration [%]
[mol%]
[%]
1
2
3
4
5
PPh3
PCy3
dppb
dpppe
dppf
26
16
89
67
24
18
8
84
66
6
N
N
1
20
20
20
13
17
23
13
16
22
N
N
N
[a] General conditions: chlorobenzene (2 mmol), potassium cyanide
(2 mmol), palladium(ii) acetate (0.04 mmol), Pd/P ˆ 1:4, MDP (0.4 mmol),
toluene (2 mL), 16 h, 1608C, in a pressure tube. [b] Conversions and yields
were determined by GC using an internal standard (diethylene glycol di-n-
butyl ether).
2
3
4
N
N
N
20
20
21
62
20
62
phosphine ligand for the cyanation reaction also depends on
the substrate used. Therefore further improvements in some
of the reported cases might be possible by changing the
phosphine ligand.
N
H
H
N
H
5
6
N
H
N
Mechanistic studies: The results shown in Table 2 and Table 4
demonstrate that different amines are effective co-catalysts
for the cyanation of a variety of aryl chlorides. The question
remaining is which elementary steps are influenced by the
addition of amine. To understand the effect of the organic co-
catalyst in more detail, we performed the palladium-catalyzed
N
20
35
35
N
7
8
20
20
67
59
66
59
N
N
N
À
C C coupling in single steps according to the generally
accepted mechanism for such reactions[18] (Scheme 2) in the
N
Pd(OAc)2
9
10
11
20
20
20
30
84
61
30
64
58
n L
base
N
N
N
N
[Pd0]
ArCN
ArX
N
N
NH2
L
L
Pd
L
12
20
31
30
NH2
Ar
Pd CN
L
Ar
X
(cis/trans)
H2N
13
14
20
10
61
71
60
66
MX
MCN
[Pd0] = Pd0Ln (n = 2-4; L = solvent, PR3, R3N, CN–)
[a] General conditions: chlorobenzene (2 mmol), potassium cyanide
(2 mmol), palladium(ii) acetate (0.04 mmol), dpppe (0.08 mmol), amine,
toluene (2 mL), 16 h, 1608C, in a pressure tube. [b] Conversions and yields
were determined by GC using an internal standard (diethylene glycol di-n-
butyl ether).
Scheme 2. Proposed mechanism for the palladium-catalyzed cyanation of
aryl halides.
presence and absence of TMEDA. The catalytic cycle starts
with the oxidative addition of the aryl halide to a Pd0 species.
À
tive with these substrates led to very low yields and
conversions.
For aryl chlorides the activation of the C X bond is more
difficult than for aryl bromides, aryl iodides, or aryl triflates.[19]
The resulting aryl palladium(ii) halide complex should
undergo an exchange of the halide by cyanide. It is possible
that this reaction step is facilitated by base (amine), by in situ
formation of the corresponding amine complex. Finally, the
aryl palladium(ii) cyanide species will reductively eliminate
the desired product (benzonitrile) and regenerate the active
Pd0 species. Because of the high temperatures, palladium
Nitrogen-containing heteroaryl chlorides (entries 20 26),
for example, 4-chloroquinaldine, 3-chloropyridine, and
2-chloro-6-methoxypyridine, reacted to give the correspond-
ing nitriles in good to excellent yields (74 91%). For
3-chloropyridine we observed higher yields when we used
dpppe as ligand instead of dppb. This result contrasted with
the reaction of chlorobenzene. Apparently, choice of the best
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M. Beller et al.
FULL PAPER
Table 4. Catalytic cyanation of various aryl chlorides[a]
Entry
1
Aryl chloride
Product
Amine
Conversion[b] [%]
99
Yield[b] [%]
86
Cl
NC
TMEDA
O
O
2
MDP
MDP
TMEDA
67
89
13
66
84
13
Cl
Cl
NC
NC
3[c]
4
5
6
MDP
TMEDA
71
22
59
12
OMe
NO2
OMe
7
8
MDP
TMEDA
62
88
53
82
Cl
NC
NO2
9
10[d]
11
MDP
MDP 66
TMEDA
46
55
32
41
24
Cl
Cl
NC
NC
12
13
MDP
TMEDA
52
25
(22)[e]
trace
N
N
F
F
14
15
MDP
TMEDA
67
11
42
10
Cl
Cl
F
NC
F
F3C
F3C
NC
16
17
MDP
TMEDA
74
11
73
11
75 (71)[e]
3
O
O
O
18
19
MDP
TMEDA
93
12
O
Cl
NC
63 (58)[e]
74 (67)[g]
N
N
20
21
MDP
TMEDA
68
76
Cl
CN
22
MDP
MDP
TMEDA
87
61
48
80
55
46
Cl
NC
23[c]
24
N
N
N
MeO
N
Cl
MeO
CN
25
26
MDP
TMEDA
95
86
91
85 (81)[e]
[a] General conditions: aryl or heteroaryl chloride (2 mmol), potassium cyanide (2 mmol), palladium(ii) acetate (0.04 mmol), dpppe (0.08 mmol), MDP
(0.4 mmol), toluene (2 mL), 16 h, 1608C, in a pressure tube. [b] Conversions and yields were determined by GC using an internal standard (diethylene glycol
di-n-butyl ether). [c] dppb instead of 1,5-bis(diphenylphosphino)pentane. [d] Reaction conditions: aryl or heteroaryl chloride (2 mmol), potassium cyanide
(2 mmol), palladium(ii) acetate (0.08 mmol), DPPPE(0.16 mmol), MDP (0.4 mmol), toluene (2 mL), 16 h, 1608C, in a pressure tube. [e] Yields of isolated
products in parentheses.
colloids may also be a catalytically active species. It is known
that such colloids, or nanoparticles, are formed from unstable
palladium phosphine complexes at high temperature and that
zotrifluoride in the presence of different cyanide concentra-
tions. To obtain a controlled amount of cyanide ions in
solution, tetra-n-butylammonium cyanide was used as the
soluble cyanide source. [Pd(PPh3)4] was chosen as a model
catalyst for two reasons: a) the complex catalyzes the
cyanation of aryl chlorides to some extent (as shown in
Table 3); and b) the more reactive Pd0 dpppe and Pd0 dppb
complexes have not been isolated in pure form, because they
easily undergo formation of dimeric and oligomeric species,
which significantly complicate the interpretation of the NMR
data.
The NMR studies were performed in standard NMR tubes.
In all experiments tetrakis(triphenylphosphine)palladium(0)
and five equivalents of 4-bromobenzotrifluoride were dis-
solved in [D8]toluene. 31P and 1H NMR were performed
immediately after addition of the respective amount of tetra-
[20]
À
they show catalytic activity in C C coupling reactions.
However, our reaction mixtures were the pale yellow that is
typical of the palladium phosphine complexes discussed here.
Takagi et al. proposed the involvement of some PdII cyanide
complexes as cyanide carriers for the formation of the aryl
palladium(ii) cyanide.[21] Despite the simplicity of this mech-
anism and the analogy to similar coupling reactions, there
should be some concern about its viability, because so far we
know of no report on the isolation of an aryl palladium(ii)
cyanide complex, and no detailed study on oxidative additions
of Pd0 complexes to aryl halides in cyanation reactions.
Therefore we investigated, by 1H and 31P NMR spectroscopy,
the stoichiometric reaction of [Pd(PPh3)4] with 4-bromoben-
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Pd-Catalyzed Cyanation of Aryl Chlorides
1828 1836
n-butylammonium cyanide. Then, within minutes, the reac-
tion mixtures were heated from room temperature to 808C, at
which temperature NMR data were collected every 45 min.
The oxidative addition proceeded smoothly at room temper-
ature in the absence of cyanide ions (Figure 2a).[22] In addition
to the signal of [Pd(PPh3)4] at d ˆ 13.1 ppm, a second signal
appeared at d ˆ 24.4 ppm, belonging to the oxidative addition
product trans-bromo[4-(trifluoro-
detected. It is clear that the presence of cyanide ions
dramatically decreases the reactivity of palladium(0) com-
plexes towards oxidative addition by replacing PPh3. In the
presence of one equivalent of cyanide (with respect to the
palladium complex) the oxidative addition was slowed down,
but it still worked at higher temperatures. In the presence of
1
five equivalents no reaction was observed. H NMR inves-
methyl)phenyl]bis(triphenylphos-
phine)palladium(ii). Because the
liberated triphenylphosphine is in
rapid equilibrium with the coordi-
nated triphenylphosphine in the
[Pd(PPh3)4], two different signals
are not observed; only a shift of
the [Pd(PPh3)4] signal to high
fields occurs (the more ™free∫
phosphine is present in the solu-
tion, the larger this shift to high
fields). Upon heating to 808C the
reaction was completed and the
formation of ™free∫ PPh3 was ob-
served at d ˆ À3.4 ppm. In the
presence of one equivalent of
cyanide (Figure 2b) no oxidative
addition was observed at room
temperature. Instead, a significant
broadening and shift of the
[Pd(PPh3)4] signal from d ˆ 13.1
to 0.7 ppm were observed. This
can be explained easily by ligand-
exchange reactions of [Pd(PPh3)4]
with cyanide ions. The increased
concentration of PPh3 accounts for
the shift of the signal towards
noncoordinated (™free∫) PPh3
(d ꢀÀ 4 ppm). When the mixture
was heated to 808C the formation
of
trans-bromo[4-(trifluorome-
thyl)phenyl]bis(triphenylphosphi-
ne)palladium(ii) (d ˆ 24 ppm) and
PPh3 (d ˆ À3.5 ppm) was ob-
served. Interestingly, GC analysis
of the NMR mixture after the
reaction revealed the formation
of 4-cyanobenzotrifluoride.
In the presence of a fivefold
excess of cyanide ions, already at
room temperature no signal for
[Pd(PPh3)4] could be observed.
The only clear detectable signal
belonged to PPh3 (d ˆ À3.7 to
À4.9 ppm). If the mixture was
heated to 1008C no formation of
the oxidative addition product was
observed. GC/MS analysis of the
reaction mixture also showed no
product formation; only 4-bromo-
benzotrifluoride and PPh3 were
Figure 2. 31P NMR spectra of the oxidative addition of [Pd(PPh3)4] to 4-bromobenzotrifluoride in the
presence of different amounts of nBu4NCN: a) without added cyanide; b) in the presence of one equivalent of
cyanide; c) in the presence of five equivalents of cyanide.
Chem. Eur. J. 2003, 9, No. 8
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1833

M. Beller et al.
FULL PAPER
tigations of the oxidative addition reaction at different
cyanide concentrations produced similar results. Different
palladium(0) cyanide complexes were most probably formed,
which were in equilibrium with each other. Therefore no
defined signal was observed.
possible. This beneficial effect of TMEDA might be useful for
other types of palladium-catalyzed coupling reactions, too.
Conclusion
As we showed, the use of TMEDA as co-catalyst leads to
improved yields of 4-cyanobenzotrifluoride in the palladium-
catalyzed cyanation of 4-chlorobenzotrifluoride.[16] Therefore,
we performed the same NMR studies of the model reaction in
the presence of a 10-fold excess of TMEDA; this resembles
the conditions of the catalytic reactions. Somewhat disap-
pointingly, no difference was seen in the 31P NMR and
1H NMR spectra. Whereas in the presence of one equivalent
of cyanide the signal of the arylpalladium(ii) complex
appeared again at d ˆ 24 ppm, no signal of the oxidative
addition product was observed in the presence of five
equivalents of cyanide ions. Apparently, the addition of
TMEDA had no effect on the oxidative addition. However, a
closer GC/MS examination of the NMR mixture after the
reaction detected, surprisingly, in addition to 4-bromobenzo-
trifluoride and PPh3, the desired product (4-cyanobenzotri-
fluoride) in 45% yield! The addition of TMEDA doubtless
prevents deactivation of the palladium(0) complex. We
assume that the amine is capable of substituting cyanide ions
on the palladium center, thereby regenerating an active
palladium catalyst. Moreover, it is evident that the arylpalla-
dium(ii) halide complex formed in situ reacts immediately
with cyanide to give the corresponding benzonitrile and a
palladium(0) complex. Hence, the second and third elemen-
tary steps in the catalytic cycle, transmetalation and reductive
elimination, must be much faster than the oxidative addition.
It should be kept in mind that these are model studies, as the
actual catalysis takes place at 1608C. To prove whether
TMEDA also has a beneficial effect on one of these latter
steps of the catalytic cycle, we studied the reaction of trans-
bromo[4-(trifluoromethyl)phenyl]bis(triphenylphosphine)-
palladium(ii) with an excess of tetra-n-butylammonium cya-
nide in toluene (Scheme 3).
These results demonstrate that the palladium-catalyzed
cyanation of nonactivated and activated aryl chlorides with
KCN is possible in good yields and selectivities in the
presence of chelating phosphine ligands and new amine co-
catalysts. This procedure for the first time allows the use of
simple alkali cyanides for a general palladium-catalyzed
cyanation of chloroarenes. Thus, it represents an important
advance in this area. On the basis of NMR studies we
conclude that the amine co-catalyst prevents deactivation of
Pd0 complexes caused by cyanide ions and increases the
stability of the phosphine ligand. In addition, we observed
that aryl palladium cyanide formation and reductive elimi-
nation were significantly faster than the oxidative addition.
Owing to the importance of the concentration of cyanide in
solution, caution should be exercised regarding the crystallite
size of the cyanide source and the purity of the solvents.[24]
Experimental Section
General: All chemicals were commercially available and used without
further purification. Potassium cyanide (Fluka) was dried in vacuo and
stored under argon. The KCN crystallites used measured 120 nm.
General procedure: In an ACE pressure tube (Aldrich) aryl chloride
(2 mmol), potassium cyanide (2 mmol), TMEDA (0.4 mmol), palladium(ii)
acetate (0.04 mmol), dpppe (0.08 mmol), and toluene (2 mL) were stirred
under argon at 1608C for 16 h. After cooling, the internal standard
(diethylene glycol di-n-butyl ether) was added, and the mixture was diluted
with dichloromethane (2 mL) and washed with water (2 mL). The organic
layer was dried over sodium sulfate and analyzed by gas chromatography.
Products were isolated by column chromatography.
NMR experiments: In a 5 mm NMR tube containing [Pd(PPh3)4] (29 mg,
0.025 mmol) and tetra-n-butylammonium cyanide (1st experiment: 0 mg;
2nd experiment: 6.7 mg, 0.025 mmol; 3rd experiment: 33.5 mg,
0.125 mmol), 4-bromobenzotrifluoride (17.5 mL, 0.125 mmol), and [D8]tol-
uene (1 mL) were added under argon. After the mixture was heated from
room temperature to 808C/1008C, 1H and 31P NMR spectra were measured
every 45 min. Finally, the reaction mixture was analyzed by GC/MS.
In both reactions 4-cyanobenzotrifluoride was obtained in
good yield (70 72% with respect to the complex used). The
yield of the product was not changed, but the selectivity of the
reaction was influenced significantly by the presence of the
amine co-catalyst. Without TMEDA, 70% benzonitrile (with
respect to the complex used) was produced, demonstrating
the low stability of triphenylphosphine towards ligand degra-
dation (aryl aryl scrambling).[23] In the presence of TMEDA
this side reaction was reduced significantly. Thus, only 18% of
benzonitrile was observed. Again, this unexpected result
might be explained by ligand exchange reactions of TMEDA.
Here, a substitution of triphenylphosphine by TMEDA is
Stoichiometric reaction of trans-bromo[4-(trifluoromethyl)phenyl]bis(tri-
phenylphosphine)palladium(ii): In an ACE pressure tube (Aldrich) trans-
bromo[4-(trifluoromethyl)phenyl]bis(triphenylphosphine)palladium(ii)
(171 mg, 0.20 mmol), triphenylphosphine (105 mg, 0.40 mmol), TMEDA
(1st experiment: 0 mL; 2nd experiment: 302 mL, 2.0 mmol), tetra-n-
butylammonium cyanide (536 mg, 2.0 mmol), and toluene (2 mL) were
stirred under argon at 1608C for 16 h. After the mixture had been cooled,
the internal standard (diethylene glycol di-n-butyl ether) was added, then
the mixture was diluted with dichloromethane (1 mL) and washed with
PPh3
Pd
2 equiv PPh3
Br
CF3
+ 10 equiv nBu4NCN
+
NC
CF3
NC
2 mL toluene
160 °C; 16h
PPh3
0.2 mmol
no co-catalyst:
10 equiv TMEDA:
0.14 mmol
0.14 mmol
0.14 mmol
0.04 mmol
Scheme 3. Stoichiometric reaction of trans-bromo[4-(trifluoromethyl)phenyl]bis(triphenylphosphine)palladium(ii) with tetra-n-butylammonium cyanide.
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 0947-6539/03/0908-1834 $ 20.00+.50/0 Chem. Eur. J. 2003, 9, No. 8
1834

Pd-Catalyzed Cyanation of Aryl Chlorides
1828 1836
water (3 mL). The organic layer was dried over sodium sulfate and
analyzed by gas chromatography.
[1] a) J. G., de Vries, Can. J. Chem. 2001, 79, 1086 1092; b) M. Beller, A.
Zapf, W. M‰gerlein, Chem. Eng. Technol. 2001, 24, 575 582; c) A.
Zapf, M. Beller, Top. Catal. 2002, 19, 101 109.
Analytical data
[2] a) W. A. Herrmann, C. Bro˚mer, K. ÷fele, T. Priermeier, M. Beller,
H. Fischer, Angew. Chem. 1995, 107, 1989 1992; Angew. Chem. Int.
Ed. Engl. 1995, 34, 1844 1848; b) M. Beller, H. Fischer, W. A.
Herrmann, C. Bro˚mer, Angew. Chem. 1995, 107, 1992 1993; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1848 1849; c) M. Beller, T. H.
Riermeier, S. Haber, H.-J. Kleiner, W. A. Herrmann, Chem. Ber.
1996, 129, 1259 1264; d) M. Beller, T. H. Riermeier, Tetrahedron
Lett. 1996, 37, 6535 6538; e) W. A. Herrmann, C. Bro˚mer, C.-P.
Reisinger, K. ÷fele, M. Beller, T. H. Riermeier, Chem. Eur. J. 1997, 3,
1357 1364; f) M. Beller, T. H. Riermeier, C.-P. Reisinger, W. A.
Herrmann, Tetrahedron Lett. 1997, 38, 2073 2074; g) M. Beller, T. H.
Riermeier, Eur. J. Inorg. Chem. 1998, 29 35; h) M. Beller, T. H.
Riermeier, W. M‰gerlein, T. E. M¸ller, W. Scherer, Polyhedron 1998,
17, 1165 1176; i) G. Stark, T. H. Riermeier, M. Beller, Synth.
Commun. 2000, 30, 1703 1711; j) A. Zapf, M. Beller, Chem. Eur. J.
2001, 7, 2908 2915.
[3] Selected examples: a) A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110,
3586 3587; Angew. Chem. Int. Ed. 1998, 38, 3387 3388; b) D. W.
Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120, 9722
9723; c) J. P. Wolfe, S. L. Buchwald, Angew. Chem. 1999, 111, 2570
2573; Angew. Chem. Int. Ed. 1999, 39, 2413 2416; d) J. P. Wolfe, R. A.
Singer, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
9550 9561; e) X. Bei, H. W. Turner, W. H. Weinberg, A. S. Guram, J.
Org. Chem. 1999, 64, 6797 6803; f) A. F. Littke, G. C. Fu, J. Org.
Chem. 1999, 64, 10 11; g) K. H. Shaughnessy, P. Kim, J. F. Hartwig, J.
Am. Chem. Soc. 1999, 121, 2123 2132; h) J. F. Hartwig, M. Kawat-
sura, S. I. Hauck, K. H. Shaughnessy, L. M. Alcazar-Roman, J. Org.
Chem. 1999, 64, 5575 5580; i) X. Bei, T. Uno, J. Norris, H. W. Turner,
W. H. Weinberg, A. S. Guram, Organometallics 1999, 18, 1840 1853;
j) A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020
4028; k) J. P. Wolfe, H. Tomori, J. P. Sadighi, J. J. Yin, S. L. Buchwald,
4-Cyanoquinaldine: 1H NMR (400 MHz, CDCl3, 297 K): d ˆ 8.07 (dd,
3J(H,H) ˆ 8.3 Hz, 4J(H,H) ˆ 0.8 Hz, 1H), 8.04 (d, 3J(H,H) ˆ 8.5 Hz,
1H), 7.77 (dt, 3J(H,H) ˆ 7.7 Hz, 4J(H,H) ˆ 1.4 Hz, 1H), 7.63 (dt, 3J(H,H)
4
ˆ 7.6 Hz, J(H,H) ˆ 1.0 Hz, 1H), 7.56 (s, 1H), 2.75 ppm (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3, 297 K): d ˆ 158.8, 148.2, 131.5, 129.9, 128.6,
‡
126.2, 125.1, 124.3, 119.2, 116.1, 25.6 ppm; MS (70 eV, EI): m/z: 168 [M ],
‡
153 [M À CH3], 140; IR (KBr): nÄ ˆ 3067, 2230, 1594, 1560, 1503, 1408,
1383, 1323, 894, 756 cmÀ1; elemental analysis (%) calcd for C11H8N2: C
78.55, H 4.79, N 16.66; found: C 78.77, H 4.87, N 16.61.
5-Cyanoindole: 1H NMR (400 MHz, CDCl3, 297 K): d ˆ 8.99 (bs, 1H), 7.98
(d, 4J(H,H) ˆ 1.6 Hz, 1H), 7.48 (d, 3J(H,H) ˆ 8.4 Hz, 1H), 7.37 (dd,
3J(H,H) ˆ 8.4 Hz, 4J(H,H) ˆ 1.6 Hz, 1H), 7.32 (d, 3J(H,H) ˆ 3.5 Hz,
1H), 6.59 ppm (d, 3J(H,H)
ˆ
3.5 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3, 297 K): d ˆ 137.6, 127.6, 126.7, 126.3, 124.6, 121.1, 112.14, 103.1,
‡
‡
102.2 ppm; MS (70 eV, EI): m/z: 142 [M ], 115 [M À HCN]; elemental
analysis (%) calcd for C9H6N2: C 76.04, H 4.25, N 19.71; found: C 76.45, H
4.47, N 19.26.
2-Cyano-6-methoxypyridine: 1H NMR (400 MHz, CD2Cl2, 297 K): d ˆ 7.68
(dd, 3J(H,H) ˆ 7.3 Hz and 8.5 Hz, 1H), 7.31 (dd, 3J(H,H) ˆ 7.3 Hz,
4J(H,H) ˆ 0.8 Hz, 1H), 6.98 (dd, 3J(H,H) ˆ 8.5 Hz, 4J(H,H) ˆ 0.8 Hz,
1H), 3.94 ppm (s, 3H); 13C{1H} NMR (101 MHz, CD2Cl2, 297 K): d ˆ
164.7, 139.5, 130.6, 122.6, 117.7, 116.4, 54.3 ppm; MS (70 eV, EI): m/z: 134
‡
‡
‡
[M ], 133, 104 [M À CH2O], 77 [M À CH2O À HCN], 40; IR (KBr): nÄ ˆ
3002, 2949, 2915, 2853, 2225, 1603, 1465, 1131, 1028 cmÀ1; elemental analysis
(%) calcd for C7H6N2O: C 62.68, H 4.51, N 20.88; found: C 62.29, H 4.57, N
20.48.
Methyl 2-cyanobenzoate: 1H NMR (400 MHz, CDCl3, 297 K): d ˆ 8.09
8.14 (m, 1H), 7.76 7.81 (m, 1H), 7.61 7.68 (m, 2H), 3.97 ppm (s, 3H);
13C{1H} NMR (101 MHz, CDCl3, 297 K): d ˆ 164.4, 134.8, 132.7, 132.4,
‡
132.3, 131.1, 117.5, 112.9, 52.8 ppm; MS (70 eV, EI) m/z: 161 [M ], 130, 102
¬
J. Org. Chem. 2000, 65, 1158 1174; l) M. Gomez Andreu, A. Zapf, M.
‡
‡
‡
[M À COOCH3], 89, 77 [C6H5 ], 51 [C4H3 ]; elemental analysis (%) calcd
Beller, Chem. Commun. 2000, 2475 2476; m) S.-Y. Liu, M. J. Choi,
G. C. Fu, Chem. Commun. 2001, 2408 2409; n) A. F. Littke, G. C. Fu,
J. Am. Chem. Soc. 2001, 123, 6989 7000; o) L. M. Alcazar-Roman,
J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 12905 12906; p) G. Y. Li,
Angew. Chem. 2001, 113, 1561 1564; Angew. Chem. Int. Ed. 2001, 40,
1513 1516; q) M. L. Clark, D. J. Cole-Hamilton, J. D. Woollins, J.
Chem. Soc. Dalton Trans. 2001, 2721 2723; r) R. B. Bedford, C. S. J.
Cazin, Chem. Commun. 2001, 1540 1541; s) M. Feuerstein, H.
Doucet, M. Santelli, J. Org. Chem. 2001, 66, 5923 5925; t) A. R.
Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131 209, and
references therein; u) A. F¸rstner, A. Leitner, Angew. Chem. 2002,
114, 632 635; Angew. Chem. Int. Ed. 2002, 41, 609 612; v) G. Y. Li,
W. J. Marshall, Organometallics 2002, 21, 590 591.
for C9H7NO2: C 67.07, H 4.38, N 8.69; found: C 67.14, H 4.31, N 8.97.
All other cyanation products are commercially available. In these cases
reaction products were identified by comparison with authentic samples
using GC/MS methods.
trans-Bromo[4-(trifluoromethyl)phenyl]bis(triphenylphosphine)palladi-
um(ii): [Pd(PPh3)4] (5.8 g, 5 mmol) was suspended in toluene (20 mL) and
4-bromobenzotrifluoride (2.8 mL, 20 mmol) was added under argon. The
mixture was stirred for 4 h at 808C and, after cooling to room temperature,
evaporated under reduced pressure. The crude reaction product was
purified by washing with diethyl ether and crystallization from dichloro-
methane/n-pentane. 1H NMR (400 MHz, CD2Cl2, 297 K): d ˆ 7.50 7.53
(m, 12H), 7.36 7.40 (m, 6H), 7.26 7.31 (m, 12H), 6.76 (d, 3J(H,H) ˆ
8.1 Hz, 2H), 6.41 ppm (d, 3J(H,H) ˆ 8.1 Hz, 2H); 13C{1H} NMR
(101 MHz, CD2Cl2, 297 K): d ˆ 136.3, 135.0, 131.4, 130.4, 128.3,
123.6 ppm; 31P{1H} NMR (162 MHz, CD2Cl2, 297 K): d ˆ 24.24 ppm; MS
[4] A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. 2000, 112, 4315
4317; Angew. Chem. Int. Ed. 2000, 39, 4153 4155.
[5] A. Ehrentraut, A. Zapf, M. Beller, Synlett 2000, 1589 1592.
[6] A. Ehrentraut, A. Zapf, M. Beller, J. Mol. Cat. 2002, 182 183, 515
523.
‡
‡
‡
(NBA, FAB): m/z: 855 [M À 1], 775 [M À 1 À Br], 630 [M À 1 À BrÀ
‡
‡
‡
PhCF3], 407 [PPh3(C6H4CF3) ], 339 [PPh4 ], 262 [PPh3 ]; IR (Nujol): nÄ ˆ
3054, 1586, 1480, 1437, 1322, 1158, 1111, 1096, 1069, 1010, 817, 745, 726, 693,
519, 495 cmÀ1; elemental analysis (%) calcd for C43H34BrF3P2Pd: C 60.34, H
4.00, Br 9.33, P 7.24, Pd 12.43; found: C 60.01, H 4.27, Br 9.71, P 7.25, Pd
12.12.
[7] A. Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Cat. 2002, 344, 209
217.
[8] a) W. M‰gerlein, A. Indolese, M. Beller, Angew. Chem. 2001, 113,
2940 2943; Angew. Chem. Int. Ed. 2001, 40, 2856 2859; b) M. Beller,
W. M‰gerlein, A. F. Indolese, C. Fischer, Synthesis 2001, 1098 1109;
c) M. Beller, A. F. Indolese, Chimia 2001, 55, 684 687; d) W.
M‰gerlein, A. F. Indolese, M. Beller, J. Organomet. Chem. 2002,
641, 30 40.
Acknowledgement
[9] a) J. Huang, G. Grasa, S. P. Nolan,Org. Lett. 1999, 1, 1307 1309; b) C.
Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org. Chem. 1999, 64,
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The authors thank Dr. A. Spannenberg (X-ray of trans-bromo[4-(trifluoro-
methyl)phenyl]bis(triphenylphosphine)palladium(ii); IfOK), Mrs. H. Bau-
disch (GC/MS; IfOK), and Dr. A. Kˆckritz (KCN crystallite measurement;
¬
ACA Berlin) for analytical support. Dr. H.-P. Krimmer and Dr. M. Gomez
Andreu (Degussa AG) are thanked for general discussions. Generous
support of this project from Degussa AG(formerly SKW Trostberg AG),
the State of Mecklenburg-Western Pomerania, the Fonds der Chemischen
Industrie, and the Bundesministerium f¸r Bildung und Forschung (BMBF)
is gratefully acknowledged. OMGis thanked for generous gifts of
palladium compounds.
Chem. Eur. J. 2003, 9, No. 8
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0908-1835 $ 20.00+.50/0
1835

M. Beller et al.
FULL PAPER
Organometallics 2001, 20, 3848 3850; i) E. Peris, J. A. Loch, J. Mata,
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2002, 4, 3031 3033.
[15] F. Jin, P. N. Confalone, Tetrahedron Lett. 2000, 41, 3271 3273.
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[17] A. J. Ewins, US 2510047, 1950.
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¬
schen Chemie, Vol. 17 (Eds.: E. Bartholome, E. Biekert, H. Hellmann,
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¡
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[22] The very small signal at d ˆ 24 25 ppm, which we observed in every
31P NMR experiment, seems to result from the NMR apparatus used.
[23] a) K.-C. Kong, C.-H. Cheng, J. Am. Chem. Soc. 1991, 113, 6313 6315;
b) W. A. Herrmann, C. Bro˚mer, K. ÷fele, M. Beller, H. Fischer, J.
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metallics 2000, 19, 1888 1900.
[24] The concentration of cyanide in solution is influenced by the solvent
purity and the size of the KCN crystals. Indeed, when we used
different charges of KCN (same purity, same supplier), reproducibility
was sometimes a problem. By measuring the crystallite size we
discovered that 120 nm KCN crystals gave much better results than
60 nm KCN crystallites. All catalytic experiments described in this
paper were performed with 120 nm KCN and we recommend use of
this crystallite size.
[13] For the palladium-catalyzed cyanation of aryl halides, see: a) K.
Takagi, T. Okamoto, Y. Sakakibara, A. Ohno, S. Oka, N. Hayama,
Bull. Chem. Soc. Jpn. 1975, 48, 3298 3301; b) K. Takagi, T. Okamoto,
Y. Sakakibara, A. Ohno, S. Oka, N. Hayama, Bull. Chem. Soc. Jpn.
1976, 49, 3177 3180; c) J. R. Dalton, S. L. Regen, J. Org. Chem. 1979,
44, 4443 4444; d) Y. Akita, M. Shimazaki, A. Ohta, Synthesis 1981,
974 975; e) Y. Anderson, B. Langstrˆm, J. Chem. Soc. Perkin Trans. 1
1994, 1395 1400; f) B. A. Anderson, E. C. Bell, F. O. Ginah, N. K.
Harn, L. M. Pagh, J. P. Wepsiec, J. Org. Chem. 1998, 63, 8224 8228.
[14] H. Hugl (Bayer AG), Presentation at the conference 50Years of
Catalysis Research in Rostock, July 1 3 2002, Rostock; see also:
a) M.-H. Rock, A. Merhold (Bayer AG), DE 19706648 A1, 1997;
b) M.-H. Rock, A. Merhold (Bayer AG), US 6162942, 2000.
Received: October 18, 2002
Revised: December 18, 2002 [F4515]
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