A convenient procedure for the palladium-catalyzed cyanation of aryl halides

Article abstract of DOI:10.1002/anie.200250778

A useful source of cyanide for the palladium-catalyzed cyanation of aryl halides is acetone cyanohydrin (see scheme; dpppe = 1,5-bis(diphenylphosphanyl) pentane, tmeda = N,N,N′,N′-tetramethylethylenediamine). The key to the success of the reaction is the slow dosage of the cyanation reagent to the reaction mixture to prevent the deactivation of the palladium catalyst caused by excess cyanide ions in solution.

Full text of DOI:10.1002/anie.200250778

Angewandte
Chemie
Synthesis of Benzonitriles
A Convenient Procedure for the Palladium-
Catalyzed Cyanation of Aryl Halides**
Mark Sundermeier, Alexander Zapf, and
Matthias Beller*
Benzonitriles are of substantial interest in organic chemistry
as integral ingredients of dyes, herbicides, natural products,
[
1]
agrochemicals, and pharmaceuticals. In addition, they
represent versatile intermediates for further transformations
in synthetic organic chemistry. An elegant method for the
preparation of benzonitriles is the transition-metal-catalyzed
[
2,3]
cyanation of aryl halides.
Recently, we reported a new,
generally applicable palladium catalyst system for the cyan-
ation of aryl and heteroaryl chlorides to the desired nitriles in
good yields using potassium cyanide as the source of
[
4]
cyanide. The main problem of this and other reported
palladium- or nickel-catalyzed cyanation protocols is catalyst
deactivation by an excess of dissolved cyanide ions in the
[
3b,4b]
reaction mixture (Scheme 1).
tivity is comparably low in cyanation reactions (TON typically
Therefore, catalyst produc-
1
0–50) compared to other palladium-catalyzed coupling
[
5]
reactions (TON 10000 to 100000).
We thought that a continuous addition of cyanide could
provide a general solution to the problem of inhibition of the
catalyst by cyanide ions. Surprisingly, the constant dosage of
cyanide has, to the best of our knowledge, never been
described for the palladium-catalyzed cyanation of aryl
halides. This might be explained because of the difficulties
associated with the dosage of solid cyanide salts. A liquid
cyanation reagent would be clearly favorable. One of the
simplest soluble cyanide sources for this reaction is acetone
cyanohydrin, which is cheap and commercially available on a
[
6]
large scale (Scheme 2). To date, the use of acetone
cyanohydrin as a cyanide source has been described only for
[
7]
nickel-catalyzed cyanation reactions and other transition-
metal-catalyzed reactions of epoxides, aldehydes, and
[
8]
dienes.
A slow and reproducible dosage of acetone cyanohydrin is
a prerequisite for successful coupling reactions, as a result of
the sensitivity of the palladium catalyst to cyanide ions.
Clearly, the dosage of the cyanide should not be significantly
[
*] Prof. Dr. M. Beller, Dr. M. Sundermeier, Dr. A. Zapf
Leibniz-Institut für Organische Katalyse an der
Universität Rostock e.V.
Buchbinderstr. 5–6, 18055 Rostock (Germany)
Fax: (+49)381-4669324
E-mail: matthias.beller@ifok.uni-rostock.de
[**] The authors thank Mrs. H. Baudisch (IfOK) for analytical support
(GC–MS). Dr. S. Weiss, Dr. J. Sans, Dr. H.-P. Krimmer, and Dr. M.
Gómez Andreu (Degussa AG) are thanked for general discussions.
Generous support for this project from the state Mecklenburg-
Western Pomerania, the Fonds der Chemischen Industrie, and the
Bundesministerium für Bildung und Forschung (BMBF) is gratefully
acknowledged. We thank OMG for providing us with palladium
compounds.
Angew. Chem. Int. Ed. 2003, 42, 1661 – 1664
DOI: 10.1002/anie.200250778
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1661

Communications
Pd(OAc)2
base
quantitative yield without any by-product being
observed! This is the first example of a palla-
dium-catalyzed cyanation of aryl halides using
acetone cyanohydrin as the cyanide source.
Table 1, entries 2 and 3show that a reduction
of the reaction temperature is possible to some
extent without any loss of catalytic productivity.
Even at 808C 4-cyanobenzotrifluoride is formed
almost quantitatively. However, at 608C
fast + CN–
n L
[
Pd(CN)n](n–2) –
n = 2–4
0
Pd Ln
fast + CN–
(Table 1, entry 4) the catalytic activity breaks
down, probably because the oxidative addition
becomes more difficult (Scheme 1).
ArCN
0
n–
ArX
[
Pd (CN)n] species
n = 2–4
Regarding the feasibility of a larger-scale
application of this protocol, the most important
point is the reduction of the catalyst/substrate
ratio. As shown in Table 1, entries 5 and 6, a
decrease in the catalyst concentration to
L
L
Ar
Pd CN
L
Ar
Pd
X
0
.5 mol% is possible without any loss of yield.
However, at a concentration of 0.1 mol% of Pd,
a higher phosphane/palladium ratio and a slower
addition of acetone cyanohydrin are required to
keep the catalyst active. The corresponding
nitrile is formed in 80% yield, which corre-
sponds to a TON of 800 (Table 1, entry 8). A
further improvement of the catalyst activity is
shown in entry 10. The cyanation proceeds
efficiently with only 0.05 mol% palladium(ii)
L
MX
MCN
Scheme 1. Proposed reaction mechanism of the palladium-catalyzed cyanation of aryl
halides.
OH
acetone cyanohydrin
O
+
HCN
Pd(OAc) , dpppe, tmeda,
2
CN
F3C
Br
F3C
CN
Na2CO3, DMAc
Scheme 2. Acetone cyanohydrin, a useful HCN equivalent.
Scheme 3. Palladium-catalyzed cyanation of 4-bromobenzotrifluoride
with acetone cyanohydrin.
faster than its consumption in order to prevent an increase in
the cyanide concentration. By using a syringe pump, which
guarantees a continuous addition of small volumes, this is
easily possible. As shown in Table 1, entry 1, the cyanation of
acetate by increasing the phosphane/palladium ratio up to 16.
Under these conditions, 4-trifluoromethylbenzonitrile is
obtained in excellent yield (95%; TON 1900) and selectivity
(98%). This corresponds to the highest TON reported for a
4
-bromobenzotrifluoride with acetone cyanohydrin proceeds
smoothly using our previously optimized catalyst system at
208C (Scheme 3). The corresponding nitrile is obtained in
[
9]
1
palladium-catalyzed cyanation of aryl bromides.
With these encouraging results in hand
we were interested in the scope and limita-
tion of our new protocol. Table 2 shows a
Table 1: Palladium-catalyzed cyanation of 4-bromobenzotrifluoride using acetone cyanohydrin.[a]
Entry
Pd(OAc)2
mol%]
Pd/P
tmeda
[mol%]
Dosage rate
t
[h]
T
[8C]
Conversion
[%]
Yield variety of different aryl halides tested in the
[
b]
À1
[c]
[c]
[
[mmolh
]
[%]
palladium-catalyzed cyanation with acetone
cyanohydrin using a relatively low catalyst
loading (0.5 mol% Pd) (Scheme 4).
Activated aryl bromides such as 4-bro-
mobenzotrifluoride, 4’-bromoacetophenone,
and methyl 4-bromobenzoate were con-
verted into the desired nitriles at 1008C
with excellent yields (> 95%; Table 2,
entries 1–3). No side products were observed
1
2
3
4
5
6
7
8
9
2
2
2
2
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:8
1:8
1:16
20
20
20
20
20
10
10
10
–
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.05
0.05
21
21
21
21
21
21
21
42
42
42
120
100
80
100
100
100
1
100
100
0
81
8
97
ꢀ99
ꢀ99
ꢀ99
1
ꢀ99
ꢀ99
0
60
1
100
100
120
120
120
140
0.5
0.1
0.1
0.1
0.05
80
0
1
0
10
95 under these conditions. 4-Bromofluoroben-
zene requires a slightly higher reaction
temperature for excellent conversion and
selectivity (1208C; Table 2, entry 4). Unac-
tivated and deactivated (electron-rich) aryl
[
2
a] General conditions: 4-bromobenzotrifluoride (2 mmol), acetone cyanohydrin solution (1m ,
.1 mmol), 1,5-bis(diphenylphosphanyl)pentane (dpppe), sodium carbonate (2.1 mmol), N,N-
dimethylacetamide (DMAc, 2 mL). [b] N,N,N’,N’-Tetramethylethylenediamine (tmeda). [c] Conversions
and yields were determined by GC using an internal standard (diethyleneglycol di-n-butyl ether).
1
662
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Angew. Chem. Int. Ed. 2003, 42, 1661 – 1664

Angewandte
Chemie
Table 2: Scope of the palladium-catalyzed cyanation using acetone cyanohydrin.[a]
luene, leads to 3-cyanotoluene in more
than 99% yield (Table 2, entry 6).
Entries 7–9 show the reaction of even
more deactivated bromoanisoles. Both
meta- and para-bromoanisole give the
corresponding methoxybenzonitriles in
almost quantitative yields (> 98%). In
contrast, the sterically more congested
ortho isomer undergoes cyanation in only
Entry
Substrate
Product
T [8C]
Conversion [%][b]
Yield [%][b]
1
100
100
ꢀ99
2
3
100
100
100
100
ꢀ99
95
2
(
1% yield, even at higher temperatures
1408C).
The cyanation of N-heteroaryl bro-
4
5
120
120
98
96
96
96
mides is also possible. 3-Bromopyridine
gave the corresponding nitrile in 82%
yield at 1008C (Table 2, entry 10). 3-
Bromothiophene is a more difficult sub-
strate: the corresponding 3-cyanothio-
phene was obtained in only 46% yield
at 1408C (Table 2, entry 11). An interest-
ing substrate is 4-bromochlorobenzene.
In this case both halogen substituents can
be replaced by cyanide. Nevertheless, the
reaction was highly chemoselective: At
6
7
120
140
100
27
ꢀ99
21
8
9
120
99
99
1
008C only substitution of the bromine
atom (82% yield for 4-chlorobenzoni-
trile) is observed in the presence of
120
100
140
98
82
46
98
82
46
1
(
2
.05 equivalents of acetone cyanohydrin
Table 2, entry 12). The addition of
.1 equivalents of the cyanide precursor
at 1208C and double the amount of base
sodium carbonate) leads to 1,4-dicyano-
1
1
1
0
1
2
(
benzene in 99% yield (Table 2, entry 13).
This demonstrates that a cyanation of
aryl chlorides is also possible. Other
examples are shown in Table 2, entries 14
and 15. 4-Chlorobenzotrifluoride gave
the corresponding 4-trifluoromethylben-
zonitrile under standard reaction condi-
tions in moderate yield (45%), whereas
an increase in the amount of catalyst to
100
120
140
82
100
78
82
ꢀ99
77
1 [
c]
3
1 [
4
d]
1 [
d]
5
140
90
89
1
mol% led to the product in 77% yield.
[
2
a] General conditions: aryl or heteroaryl halide (2 mmol), acetone cyanohydrin solution (1m,
.1 mmol, dosage rate: 0.1 mLh ), palladium(ii) acetate (0.01 mmol), dpppe (0.02 mmol),
À1
In the case of 4’-chloroacetophenone, the
desired product was obtained in good
tmeda (0.2 mmol), sodium carbonate (2.1 mmol), DMAc (2 mL), 21 h. [b] Conversions and
yields were determined by GC using an internal standard (diethyleneglycol di-n-butyl ether).
yield (89%). Notably, the concentrations
of catalyst used for the cyanation of aryl
chlorides are thus far the lowest reported
À1
[c] Acetone cyanohydrin solution (1m, 4.2 mL, dosage rate: 0.1 mLh ), sodium carbonate
(
4.2 mmol ), 42 h. [d] Palladium(ii) acetate (0.02 mmol), dpppe (0.04 mmol).
in literature.
bromides require higher temperatures, too. For example, at
008C bromobenzene gives benzonitrile in just 59% yield,
but at 1208C an excellent yield of 96% is observed (Table 2,
The presented results demonstrate that the palladium-
catalyzed cyanation of a wide variety of aryl halides with
acetone cyanohydrin as the cyanide source is possible in a
very efficient manner. Substituted benzonitriles are obtained
in excellent yield and selectivity (in general > 99%) from the
corresponding aryl bromides. Also activated aryl chlorides
can be transformed into the desired products in moderate to
very good yield. The new method is more advantageous than
other known cyanation protocols with respect to catalyst
amount, reproducibility, and the absence of stoichiometric
amounts of zinc salts, which are often required for successful
cyanation reactions.
1
entry 5). A slightly deactivated aryl bromide, 3-bromoto-
1
.05 equiv acetone cyanohydrine
0.5 mol% Pd(OAc)2, 1 mol% dpppe,
10 mol% tmeda, 1.05 equiv Na2CO3
X
CN
R
DMAc, 21 h
R
X = Br, Cl
Scheme 4. Palladium-catalyzed cyanation of different aryl halides with
acetone cyanohydrin.
Angew. Chem. Int. Ed. 2003, 42, 1661 – 1664
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
With our protocol, we have shown that the deactivation of
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General: All chemicals are commercially available and were used
without further purification. Acetone cyanohydrin was used as a 1m
solution in N,N-dimethyl acetamide. Products were fully character-
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commercially available products by comparison of GC–MS data.
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4
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(
(
223mg, 2.1 mmol) and purged with argon. The aryl bromide
2 mmol), tmeda (30 mL; 0.2 mmol), catalyst solution (1 mL), and
[
10]
DMAc (1 mL) were added. The reaction mixture was heated to
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1
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À1
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cooled to room temperature, the internal standard diethyleneglycol
di-n-butyl ether (400 mL) was added, and the reaction mixture was
diluted with dichloromethane. Conversions and yields were deter-
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Received: December 16, 2002 [Z50778]
Keywords: acetone cyanohydrin · aryl halides · benzonitriles ·
.
cyanation · palladium
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664
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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