An environmentally benign procedure for the Cu-catalyzed cyanation of aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2005.02.106

The development of a general Cu-catalyzed synthesis of (hetero)aromatic nitriles from the corresponding aryl bromides and potassium hexacyanoferrate(II) is described. This novel protocol avoids the use of highly toxic alkali cyanides and precious palladium catalysts. Best results were achieved applying Cu(BF₄)₂?6H₂O (0.1 equiv) and N,N′-dimethyl ethylenediamine (DMEDA; 1.0 equiv) in N,N-dimethyl acetamide (DMAc).

Full text of DOI:10.1016/j.tetlet.2005.02.106

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2585–2588
An environmentally benign procedure for the Cu-catalyzed
cyanation of aryl bromides
Thomas Schareina, Alexander Zapf and Matthias Beller*
Leibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e.V. (IfOK), Buchbinderstr. 5-6, D-18055 Rostock, Germany
Received 13 January 2005; revised 14 February 2005; accepted 15 February 2005
Abstract—The development of a general Cu-catalyzed synthesis of (hetero)aromatic nitriles from the corresponding aryl bromides
and potassium hexacyanoferrate(II) is described. This novel protocol avoids the use of highly toxic alkali cyanides and precious pal-
ladium catalysts. Best results were achieved applying Cu(BF4)2Æ6H2O (0.1 equiv) and N,N0-dimethyl ethylenediamine (DMEDA;
1.0 equiv) in N,N-dimethyl acetamide (DMAc).
Ó 2005 Elsevier Ltd. All rights reserved.
Benzonitriles are of considerable interest for organic
synthesis as integral part of dyes, herbicides, agrochem-
icals, pharmaceuticals and natural products.1 In addi-
tion, the nitrile group serves as an important
intermediate for a multitude of transformations into
other functional groups.
+MCN
catalyst
X
CN
-MX
R
R
X = Cl, Br, I, OTf
Scheme 1. Transition metal-catalyzed cyanation of Ar–X derivatives.
Traditional methods for the preparation of benzonitriles
on laboratory as well as on industrial scale are the
Rosenmund-von Braun reaction2 of aryl halides and
the diazotization of anilines and subsequent Sandmeyer
reaction.3 For multi-ton-scale productions of less com-
plex benzonitriles toluenes are directly oxidized in the
presence of ammonia (ammoxidation).4 General prob-
lems of these procedures are the limited substrate scope
and the often drastic reaction conditions.
of cyanide ions.7,8 Hence, the use of less expensive cata-
lysts is of continuing interest. In this regard it is interest-
ing to note that the addition of copper salts has been
proven beneficial in some palladium-catalyzed cyana-
tion reactions.9 Nevertheless it was a significant progress
when Buchwald and co-workers reported the develop-
ment of a cyanation reaction for aryl bromides that is
based on the use of substoichiometric amounts of cop-
per (10 mol % copper(I) iodide) and no additional metal
catalyst.10
More recently, useful alternative procedures for the
preparation of higher substituted benzonitriles were
developed. Here, especially the transition metal-cata-
lyzed cyanations of aryl–X compounds (X = Cl, Br, I,
OTf) with cheap and readily available cyanation agents
like sodium or potassium cyanide are noteworthy
(Scheme 1).5
Apart from the catalyst the cyanide source plays an
important role for the applicability of a given cyanation
reaction. Recently, we introduced potassium hexacyano-
ferrate(II) for palladium-catalyzed cyanations of aryl
halides.11 This reagent has significant advantages com-
pared to other cyanide sources known for benzonitrile
synthesis. While alkali cyanides are highly poisonous
(e.g., KCN LDLo (oral, human) = 2.86 mg/kg), zinc cya-
nide leads to stoichiometric waste of heavy metal salts,
and trimethylsilyl cyanide is sensitive to moisture and
can easily liberate hydrogen cyanide, which is also true
for acetone cyanohydrin. On the other hand
K4[Fe(CN)6] is non-toxic (the LDLo of K4[Fe(CN)6] is
Catalysts applied for the coupling of aryl halides or tri-
flates with cyanide have been often palladium com-
plexes.6 Until very recently, the main problem of these
catalysts was productivity due to deactivation by excess
*
Corresponding author. Tel.: +49 381 466930; fax: +49 381
4669324; e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.106

2586
T. Schareina et al. / Tetrahedron Letters 46 (2005) 2585–2588
comparable to NaCl!) and even used in food industry
for metal precipitation. In addition, it has been
described as anti-agglutinating auxiliary for table salt
(NaCl). Hence, for the first time in cyanations of aryl
halides the use of toxic cyanides can be avoided. Inter-
estingly, K4[Fe(CN)6] is commercially available on ton
scale and even cheaper than KCN.12
the aryl group. As a result KBr and iron bromide salts
are formed.
At 100 °C only low yields of benzonitrile are obtained,
however, increasing the temperature to 140 °C led to
benzonitrile in up to 89% yield (Table 1, entry 4). At-
tempts to vary the copper pre-catalyst or to reduce the
amount of copper salt and KI decreased the product
yield significantly (Table 1, entries 5, 7–9). Changing
the solvent to N-methylpyrrolidinone (NMP) made basic-
ally no difference (Table 1, entry 6). Although no
detailed study of the ligand influence has been made
the use of DMEDA seems to be crucial (Table 1, entries
4, 10 and 11). On the other hand the addition of a cata-
lytic amount of an inorganic base is less important
(Table 1, entries 4, 12–14). The fact that Cu(BF4)2Æ6H2O
is—so far—the best copper catalyst for use with
K4[Fe(CN)6] as cyanide source seems to be unexpected,
but is understandable. This precursor is well soluble in
DMAc, its anion is rather inert, and the inherent crystal
water15 presumably helps to solvate the highly charged
[Fe(CN)6]4ꢀ anion in the organic solvent. Although
the resulting copper hexacyanoferrate complexes are
hardly soluble in aqueous solution and therefore used
for the precipitation of copper impurities in wine, the
catalytically active metal and the nucleophile are in
close contact to each other and may provide a
well-suited reaction environment for the cyanation
reaction.
To further improve and expand the tools for cyanation
of aryl halides, we set out to combine the advantages of
non-expensive copper catalysts with the non-toxic cya-
nide source, potassium hexacyanoferrate(II). Here, we
describe the successful development of such a novel
procedure.
As a starting point of our investigations, we applied a
catalyst system according to Buchwald (10 mol % CuI,
100 mol % N,N0-dimethyl ethylenediamine (DMEDA),
20 mol % KI) together with K4[Fe(CN)6] as cyanide
source (20 mol %, i.e., 1.2 equiv cyanide).13 In order to
ensure sufficient solubility we used dipolar aprotic sol-
vents, for example, N,N-dimethyl acetamide (DMAc)
and NMP.
The influence of different copper precursors, ligands,
temperature, solvents and additives was studied for the
cyanation of bromobenzene to benzonitrile. Selected
results of the variation of reaction parameters on this
model reaction are shown in Table 1. When using CuI
at 120 °C, a moderate yield of 62% of benzonitrile was
obtained. Cu(BF4)2Æ6H2O led to some improvement,
but the corresponding water-free catalyst did not prove
beneficial (Table 1, entries 1–3).14 Interestingly, it is not
necessary to use an excess of K4[Fe(CN)6]. Hence, basi-
cally all the cyanide ions bound to Fe are transferred to
Next, a number of aryl and heteroaryl bromides were
tested applying the optimized conditions (similar to
Table 1, entry 4). The results are described in Table 2.
Both electron-poor and electron-rich bromoarenes react
well under these conditions. Hence, 1-bromonaphthalene,
Table 1. Cyanation of bromobenzene
K4[Fe(CN)6]
Br
CN
Cu catalyst, ligand
Liganda
Entry
Cu pre-catalyst (mol %)
Temp (°C)
Conv. (%)
Yield (%)
1
CuI (10)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2 (10)
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
TMEDA
EDA
120
120
120
140
140
140
140
140
140
140
140
140
140
140
85
84
73
100
86
84
74
56
40
8
62
68
59
89
74
75
58
44
33
0
2
3
4
Cu(BF4)2Æ6H2O (10)
CuI (10)
CuI (10)
5
6b
7
Cu(OAc)2 (10)
8c
9d
10
11
12e
13f
14g
Cu(BF4)2Æ6H2O (5)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2Æ6H2O (10)
Cu(BF4)2Æ6H2O (10)
66
89
90
99
31
80
74
88
DMEDA
DMEDA
DMEDA
Reaction conditions: 2.0 mmol bromobenzene, 20 mol % dry K4[Fe(CN)6], 2 mL DMAc, 20 mol % KI, 20 mol % Na2CO3.
a 100 mol %; DMEDA = N,N0-dimethyl ethylenediamine, TMEDA = N,N,N0,N0-tetramethyl ethylenediamine, EDA = ethylene diamine.
b Solvent = NMP.
c 10 mol % KI.
d No KI.
e No Na2CO3.
f 20 mol % Et3N instead of Na2CO3.
g 20 mol % K3PO4 instead of Na2CO3.

T. Schareina et al. / Tetrahedron Letters 46 (2005) 2585–2588
Table 2. Cyanation of various aryl and heteroaryl halides
2587
+K4[Fe(CN)6]
Br
CN
R
Cu(BF4)2 · 6H2O
DMEDA
R
Entry
1
Ar–X
Ar–CN
Conv. (%)
97
Yield (%)
Br
CN
80
90
85
29
Br
CN
CN
2
3
4
94
86
54
Br
Br
CN
Br
O
CN
O
5
92
54
O
O
Br
O
O
CN
6
7
100
96
91
85
CN
Br
Br
CN
8
100
96
O
O
O
O
Br
CN
9
94
81
59
70
O
O
H2N
Br
Br
H2N
CN
CN
10
11
12
100
25
73
12
F3C
F3C
Cl
Br
CN
CN
F3C
O
F3C
O
13a
14
100
100
100
61
90
67
Br
Br
CN
CN
S
N
S
N
15
Reaction conditions: 2.0 mmol aryl halide, 20 mol % dry K4[Fe(CN)6], 2 mL DMAc, 20 mol % KI, 20 mol % Na2CO3, 100 mol % DMEDA.
a In case of 4-bromoacetophenone a side product is also formed in ca. 20% yield, which gave upon hydrolysis with water the desired product.

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T. Schareina et al. / Tetrahedron Letters 46 (2005) 2585–2588
hedron Lett. 2004, 45, 1441–1444; (b) Marcantonio, K. M.;
Frey, L. F.; Liu, Y.; Chen, Y.; Strine, J.; Phenix, B.;
Wallace, D. J.; Chen, C. Y. Org. Lett. 2004, 6, 3723–3725;
(c) Srivastava, R. R.; Collibee, S. E. Tetrahedron Lett.
2004, 45, 8895–8897; (d) Yang, C. H.; Williams, J. M. Org.
Lett. 2004, 6, 2837–2840; (e) Sundermeier, M.; Zapf, A.;
Beller, M.; Sans, J. Tetrahedron Lett. 2001, 42, 6707–6710;
(f) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41,
3271–3273.
2- and 3-bromotoluene, 3- and 4-bromoanisole, 6-meth-
oxy-2-bromonaphthalene and 3-bromothiophene gave
the corresponding benzonitriles in 80–96% yield. Highly
electron-rich substrates like 4-bromoveratrol16 and 3-
bromo-4-methylaniline are more difficult to transform.
Nevertheless, they led to the products in moderate to
good yield (59–70%) (Table 2, entries 9 and 10). How-
ever, two substituents in ortho-position lowered the yield
considerably (Table 2, entry 4).
7. For deactivation of palladium catalysts, see: Sundermeier,
M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, S.; Weiss,
S.; Beller, M. Chem. Eur. J. 2003, 9, 1828–1836.
The difference between C–Br and C–Cl activation is
demonstrated in case of 4-halobenzotrifluoride (Table
2, entries 11 and 12). While 4-bromobenzotrifluoride
performs reasonably well (73% yield), the corresponding
chloride is only slightly converted under these condi-
tions (12% yield).
8. For examples of cyanations with catalyst turnover num-
bers >1000, see: (a) Sundermeier, M.; Zapf, A.; Beller, M.
Angew. Chem. 2003, 115, 1700–1703; Angew. Chem., Int.
Ed. 2003, 42, 1661–1664; (b) Sundermeier, M.; Mutyala,
S.; Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet.
Chem. 2003, 684, 50–55; (c) Maligres, P. E.; Waters, M. S.;
Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40, 8193–
8195.
9. (a) Sato, N.; Suzuki, M. J. Heterocycl. Chem. 1987, 24,
1371–1372; (b) Anderson, B. A.; Bell, E. C.; Ginah, F. O.;
Harn, N. K.; Pagh, L. M.; Wepsiec, J. P. J. Org. Chem.
1998, 63, 8224–8228; (c) Sakamoto, T.; Ohsawa, K. J.
Chem. Soc., Perkin Trans. 1 1999, 2323–2326.
In conclusion, we have shown for the first time, that it is
possible to perform copper-catalyzed cyanations of aryl
halides using potassium hexacyanoferrate(II).17 A vari-
ety of different aryl and heteroaryl bromides gave the
corresponding benzonitriles in good yield. This novel
procedure represents a more environmentally benign
and less hazardous protocol by using the non-toxic
potassium hexacyanoferrate(II) instead of the highly
toxic alkali cyanides.
10. (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 2890–2891; For
a copper-catalyzed
cyanation of aryl iodides, see: (b) Wu, J. X.; Beck, B.;
Ren, R. X. Tetrahedron Lett. 2002, 43, 387–389.
11. (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun.
2004, 1388–1389; (b) Schareina, T.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2004, 689, 4576–4583.
Acknowledgements
12. The price per mol CNꢀ is 2.7€ for K4[Fe(CN)6] and 7.9€
for KCN; source Aldrich Chemicals Catalogue 2003.
13. General procedure: under inert conditions 0.4 mmol
Na2CO3, 0.4 mmol K4[Fe(CN)6] (K4[Fe(CN)6]Æ3H2O is
ground to a fine powder and dried in vacuum (ca. 2 mbar)
at 80 °C over night), 0.2 mmol copper precursor and
0.4 mmol KI are placed in a pressure tube. An argon
needle is inserted into the pressure tube and the solids are
flushed with argon for at least 1 min. Then 2 mmol aryl
halide, 2 mmol amine and 2 mL of a 0.1 M stock solution
of Cu(BF4)2Æ6H2O in the corresponding solvent are added.
The pressure tube is sealed and heated for 16 h at the
temperature specified in the table. After cooling to room
temperature 3 mL dichloromethane and 400 lL diethyl-
eneglycol di-n-butylether (internal standard) are added
and the mixture is analyzed by GC. The conversion and
yield are calculated as the average of two parallel runs.
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 chromatography (silica, hexane/ethyl acetate).
All prepared benzonitriles are known compounds and
identified by comparison with commercially available
materials.
This work has been supported by the State of Mecklen-
burg-Vorpommern and the Fonds der Chemischen
Industrie (FCI). We thank Dr. C. Fischer, Mrs. A. Leh-
mann, Mrs. S. Buchholz and Ms. K. Reincke (all IfOK)
for their excellent analytical support.
References and notes
1. (a) Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989; pp 819–995; (b) Grundmann, C.
In Houben-Weyl: Methoden der organischen Chemie, 4th
ed., Falbe, J., Ed., Georg Thieme: Stuttgart, 1985;
Vol. E5, 1985, pp 1313–1527.
2. Lindley, J. Tetrahedron 1984, 40, 1433–1456.
3. For a recent catalytic variant of the Sandmeyer reaction,
see: Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.;
Petrovskii, P. V. J. Organomet. Chem. 2004, 689, 3810–
3812.
4. (a) Hagedorn, F.; Gelbke, H.-P. In Ullmanns Encyklopa¨die
´
der technischen Chemie, 4th ed., Bartholome, E., Biekert,
E., Hellmann, H., Ley, H., Weigert, W. M., Weise, E.,
Eds.; Verlag Chemie: Weinheim, 1979; Vol. 17, pp 333–
338; (b) Ellis, G. P.; Romney-Alexander, T. M. Chem.
Rev. 1987, 87, 779–794.
14. Cu(BF4)2Æ6H2O was dried overnight in a desiccator over
sicapent (Merck KGaA, Darmstadt) in vacuum, then at
80 °C (melt) in vacuum.
15. Water (60 mol %) relative to the substrate are introduced
into the reaction mixture with the catalyst precursor.
16. In case of 4-bromoveratrol the reaction mixture developed
a deep purple colour. This may indicate the formation of
copper complexes from which the product is not fully
liberated.
5. (a) Tsuji, J. Transition Metal Reagents and Catalysts—
Innovations in Organic Synthesis; John Wiley: Chichester,
2000; (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H.
D. Application of Transition Metal Catalysts in Organic
Synthesis; Springer: Berlin, Heidelberg, 1999; pp 149–177;
(c) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev.
1987, 87, 779–794.
6. For a review on palladium-catalyzed cyanations, see:
Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem.
2003, 3513–3526; for some recent examples of palladium-
catalyzed cyanations, see: (a) Chidambaram, R. Tetra-
17. After submission of this manuscript Weissman et al.
reported also on the use of K4Fe(CN)6 with palladium
catalysts: Weissman, S. A.; Zwerge, D.; Chen, C. Org.
Chem. 2004, 70, 1508–1510.