Potassium hexacyanoferrate(II) - A new cyanating agent for the palladium-catalyzed cyanation of aryl halides

Article abstract of DOI:10.1039/b400562g

A new advantageous cyanating agent, potassium hexacyanoferrate(II), is described for the palladium-catalyzed cyanation of aryl halides. All cyanide ions on the iron(II) center can be transferred to the aryl halide using palladium(II) acetate and dppf as the catalyst. Under optimized reaction conditions good yields of benzonitriles and unprecedented catalyst productivities are observed.

Full text of DOI:10.1039/b400562g

Potassium hexacyanoferrate(II)—a new cyanating agent for the
palladium-catalyzed cyanation of aryl halides
Thomas Schareina, Alexander Zapf and Matthias Beller*
Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstr. 5–6, 18055
Rostock, Germany. E-mail: matthias.beller@ifok.uni-rostock.de
Received (in Cambridge, UK) 14th January 2004, Accepted 2nd April 2004
First published as an Advance Article on the web 12th May 2004
A new advantageous cyanating agent, potassium hexacyano-
ferrate(II), is described for the palladium-catalyzed cyanation of
aryl halides. All cyanide ions on the iron(II) center can be
transferred to the aryl halide using palladium(II) acetate and
dppf as the catalyst. Under optimized reaction conditions good
yields of benzonitriles and unprecedented catalyst productiv-
ities are observed.
Table 1 shows selected results that were obtained while
investigating the cyanation of bromobenzene with K4[Fe(CN)6].†
As starting point a previously developed catalyst system consisting
of palladium(II) acetate and 1,5-bis(diphenylphosphino)pentane
(dpppe) in the presence of sodium carbonate was used. While
nonpolar solvents such as toluene and dioxane are not suited for this
reaction (Table 1, entries 1 and 2), we were surprised to discover
that in DMAc or NMP benzonitrile is formed in significant yield
(49 and 56%, respectively) (Table 1, entries 3 and 4). Applying
alkali cyanides the latter solvents are not useful for the cyanation of
aryl bromides or chlorides due to the increased cyanide concentra-
tion in solution, which leads to catalyst deactivation.
Substituted benzonitriles represent important building blocks for
fine chemical synthesis. They are integral parts of dyes, natural
products, herbicides, agrochemicals, and pharmaceuticals. On a
larger scale aryl cyanides are produced mainly via ammoxidation of
the corresponding toluenes. In addition, still the Rosenmund–von
Testing different ligands in the presence of K4[Fe(CN)6]
revealed, that both monodentate and chelating phosphines are
suitable for the cyanation of bromobenzene. 1,1A-Bis(diphenyl-
phosphino)ferrocene (dppf) gave full conversion and the best yield
(81%; Table 1, entry 8), but tricyclohexylphosphine was almost as
efficient (70%; Table 1, entry 6). Advantageously, even simple
PPh3 gave a moderate yield of benzonitrile (54%; Table 1, entry 5).
Using 1 mol% of palladium catalyst reductive dehalogenation is
observed as side-reaction to a minor amount. Surprisingly, with a
decreased amount of catalyst (0.1 mol%) an even higher selectivity
and yield of benzonitrile is obtained ( > 99%; Table 1, entry 11). We
explain this behavior by a decrease of agglomeration of molecular
palladium complexes to “palladium black”, which gives less
selective reactions. A similar effect has been described by de Vries
et al. for Heck olefinations of aryl iodides.8 Even higher turnover
numbers can be realized when the reaction temperature is increased
by 20 K. In the presence of 0.01 mol% palladium 97% of
benzonitrile is formed resulting in a TON of almost 10 000 (Table
1, entry 13). This is the highest turnover number which we are
aware for a palladium-catalyzed cyanation of aryl halides. Gen-
erally, 0.25 equiv. of hexacyanoferrate(II) are applied as cyanating
agent in our reaction. This corresponds to 1.5 equivalents of
cyanide with respect to aryl halide. However, lowering the amount
Braun reaction [reaction of aryl halides with copper(
the Sandmeyer reaction [reaction of diazonium salts with copper(
cyanide] are used to a considerable extent, although very recently
also a copper-catalyzed variant has been described.1 Compared to
these classic methods transition metal-catalyzed cyanations of aryl
halides are somewhat underdeveloped.2
I
) cyanide] and
I)
In the past, both nickel3 and palladium complexes4 have been
used as catalysts for the cyanation of aryl halides. Mechanistic
studies revealed that the general problem of these reactions is the
deactivation of the transition metal catalyst by formation of too
stable cyano complexes.4a,5 Recently, we have been able to show
that catalyst deactivation can be prevented by defined control of the
concentration of dissolved cyanide ions.6 Typically this is achieved
by the use of nonpolar solvents such as toluene or xylene, that allow
only low concentrations of solubilized cyanide salts (generally
KCN or NaCN). Another way to control the Pd/cyanide ratio is the
slow dosage of liquid or soluble cyanide sources. Here, we
demonstrated that trimethylsilylcyanide7 or acetone cyanohydrin6
are suitable reagents for this purpose, which lead to an increase in
catalyst efficiency.
Despite the recent progress in palladium-catalyzed cyanations of
aryl triflates, iodides, bromides, and even chlorides all known
protocols have disadvantages and offer significant potential for
improvements. On the one hand catalyst productivities are low (in
general TON 20–400) compared to other palladium-catalyzed
coupling reactions. In addition, ortho-substituted aryl halides react
often sluggishly and give low product yields. Importantly, the
known cyanide sources have also severe drawbacks which prevent
wider application of this methodology: alkali cyanides are highly
poisonous, zinc cyanide leads to stoichiometric amounts of heavy
metal salt wastes, and TMSCN is sensitive to moisture and can
easily liberate hydrogen cyanide, which is also true for acetone
cyanohydrin. In order to overcome these problems, we were
looking for alternative cyanide sources, which are less poisonous
and can easily be handled without special precautions.
Table 1 Variation of reaction conditions for the cyanation of bromo-
benzene†
Cat.
conc.
Ligand [conc.
T
Conv. Yield
Entry Solvent (mol%) (mol%)]
(°C) (%) (%)
TON
1
2
3
4
5
6
7
8
9
10
11
12d
13
14
Toluene
Dioxane
DMAc
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
1
1
1
1
1
1
1
1
1
1
0.1
0.1
0.01
1
dpppe [2]
dpppe [2]
dpppe [2]
dpppe [2]
PPh3 [4]
PCy3 [4]
120
120
120
120
120
120
12
14
57
68
64
84
73
100
29
12
6
6
9
9
49
56
54
70
59
81
18
1
49
56
54
70
59
81
18
1
Bpephosa [2] 120
dppf [2] 120
Xantphosb [2] 120
Here, we describe for the first time the use of potassium
hexacyanoferrate(II) (K4[Fe(CN)6]) as cyanating agent for the
general synthesis of benzonitriles (Scheme 1).
Iphosc [2]
dppf [0.2]
dppf [0.2]
dppf [0.02]
dppf [2]
120
120
120
140
100
100
96
100
59
> 99 1000
92 920
97 9700
43 43
a 2,2A-Bis(diphenylphosphino)diphenyl ether. b 9,9-Dimethyl-4,5-bis(di-
phenylphosphino)xanthene. c 2,2A-Bis{bis[3,5-bis(trifluoromethyl)phenyl]-
phosphinomethyl}-1,1A-binaphthyl. d 17 mol% K4[Fe(CN)6].
Scheme 1 Cyanation of aryl halides using potassium hexacyanoferrate(II) as
cyanide source (X = Br, Cl).
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C h e m . C o m m u n . , 2 0 0 4 , 1 3 8 8 – 1 3 8 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Cyanation of various aryl halides†
and 10). 1-Bromonaphthalene yields 90% 1-cyanonaphthalene
(Table 2, entry 11). Electronically deactivated m- and p-bromoani-
sole can be cyanated with very good yield (88–95%; Table 2,
entries 12 and 13). N- and S-heterocycles such as 3-bromopyridine,
3-bromothiophene, and 4-chloroquinaldine give the desired nitriles
in 78–87% yield (Table 2, entries 14–16).
In summary, we have developed a new general protocol for the
cyanation of aryl halides. For the first time potassium hex-
acyanoferrate(II) has been used as cyanide source. The advantages
of this “coupling reagent” are obvious: in contrast to other
cyanating agents potassium hexacyanoferrate(II) is less poisonous‡
and can be handled without special precaution. Due to the slow
release of cyanide ions a significantly improved catalyst productiv-
ity compared to previously known procedures is achieved.
The authors thank Dr W. Baumann, Dr C. Fischer, Mrs S.
Buchholz and Ms K. Reincke for analytical support. Generous
support from the state Mecklenburg-Vorpommern and the Fonds
der Chemischen Industrie are gratefully acknowledged. OMG (now
Umicore) is thanked for gifts of palladium compounds.
Cat.
conc.
(mol%) (%)
T
(°C)
Conv. Yield
Entry
Aryl halide
(%)
TON
1
2
120
120
0.1
0.01
100
100
86
87
860
8700
3
100
0.1
100
78
780
4
5
120
120
0.1
0.1
98
96
94
66
940
660
6
7
120
140
0.1
0.5
60
93
51
68
510
136
Notes and references
8
120
0.1
100
95
950
†
General procedure: Under inert conditions 2.0 mmol Na2CO3, 0.5
mmol K4[Fe(CN)6] {K4[Fe(CN)6]·3H2O is ground to a fine powder and
dried in vacuum (ca. 2 mbar) at 80 °C over night}, Pd(OAc)2 and ligand are
placed in a pressure tube. Then 2.0 mmol aryl halide and 2.0 mL solvent are
added. Stock solutions of Pd(OAc)2 and ligand were used for Pd contents
smaller than 0.5%. The pressure tube is sealed and heated at 120 °C for 16
h. After cooling to room temperature 3.0 mL dichloromethane and 0.4 mL
diethylene glycol di-n-butyl ether (internal standard) are added and the
mixture is analyzed by GC. For isolating the products the reaction mixture
is washed with water and the organic phase is dried over Na2SO4. After
evaporation of the solvents the residue is subjected to column chromatog-
raphy (silica, hexane–ethyl acetate). All prepared benzonitriles are known
compounds and identified by comparison (GC/MS) with authentic samples.
9
10
120
160
0.25
0.25
48
88
41
75
164
300
11
120
0.1
100
90
900
12
13
120
120
0.1
0.1
92
88
95
880
950
100
‡
KCN is extremely toxic [LDL0 (oral, human) = 2.86 mg kg21] and
develops HCN on contact with acidic water. K4[Fe(CN)6] is nontoxic and
used in food industry for metal precipitation in wine. Also it has been used
as anti-agglutinating auxiliary for NaCl (table salt) (cf. Roempp Lexikon
Chemie – Version 2.0, Georg Thieme Verlag, Stuttgart/New York, 1999). It
is soluble in water without decomposition.
14
15
140
140
0.1
0.1
97
95
86
87
860
870
1 J. Zanon, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
2890.
16
140
0.1
91
78
780
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of the cyanide source to 0.17 equiv. still gave 92% of benzonitrile
(Table 1, entry 12). This demonstrates that all the six cyanide ions
bound to the iron(II) center are used in the cyanation reaction.
Interestingly, potassium hexacyanoferrate(III) in contrast is not
suitable as the cyanide source ( < 5% of benzonitrile), presumably
because of its oxidizing properties. Apart from Pd(OAc)2 other
palladium sources, e.g. Pd2(dba)3, performed equally well in the
model reaction. An important parameter is the reaction tem-
perature, which should not be < 120 °C (Table 1, entry 14).
Apparently at lower temperature cyanide is not transferred from the
iron center.
The new protocol was then applied to the cyanation of various
aryl halides (Table 2). In general, using 0.1 mol% catalyst at 120 °C
good to excellent yields of the desired benzonitriles are obtained. In
the case of electron deficient aryl bromides, e.g. for 4-bromoaceto-
phenone (Table 2, entries 1 and 2), even 0.01 mol% palladium are
sufficient for high yields (87%). Methyl 4-bromobenzoate (78%)
and 4-(trifluoromethyl)bromobenzene (94%) work similarly well,
while 3-bromobenzaldehyde gives 66% of 3-cyanobenzaldehyde
(Table 2, entries 3–5).
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Interestingly, also a number of ortho-substituted aryl bromides
work well in the procedure. In the case of 2,4-difluorobromo-
benzene an increase in the catalyst concentration (to 0.5 mol%) and
reaction temperature (to 140 °C) leads to an improved yield of 68%
vs. 51% (Table 2, entries 6 and 7). 2-Bromotoluene gives 95% of
2-cyanotoluene under standard conditions (Table 2, entry 8). Even
2,6-dimethylbromobenzene is converted to 2-cyano-m-xylene in
75% yield in the presence of 0.25 mol% catalyst (Table 2, entries 9
C h e m . C o m m u n . , 2 0 0 4 , 1 3 8 8 – 1 3 8 9
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