A versatile protocol for copper-catalyzed cyanation of aryl and heteroaryl bromides with acetone cyanohydrin

Article abstract of DOI:10.1002/adsc.201000200

A novel copper-catalyzed cyanation of aryl and heteroaryl bromides using acetone cyanohydrin has been developed. Copyright

Full text of DOI:10.1002/adsc.201000200

UPDATES
DOI: 10.1002/adsc.201000200
AVersatile Protocol for Copper-Catalyzed Cyanation of Aryl and
Heteroaryl Bromides with Acetone Cyanohydrin
a
a
b
b
Thomas Schareina, Alexander Zapf, Alain Cottꢀ, Matthias Gotta,
a,
and Matthias Beller *
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock, Albert-Einstein-Strasse 29 A, 18059 Rostock, Germany
Fax : (+49)-381-1281-5000; e-mail: matthias.beller@catalysis.de
a
b
Saltigo GmbH, Katzbergstr. 1, 40764 Langenfeld, Germany
Received: March 15, 2010; Revised: January 1, 2011; Published online: March 10, 2011
Abstract: A novel copper-catalyzed cyanation of
aryl and heteroaryl bromides using acetone cyano-
hydrin has been developed.
In general, it is well known for metal-catalyzed cy-
À
anations that an increased concentration of CN
[
11]
blocks the active metal center. This problem can be
circumvented by decreasing the solubility of cyanide
in the respective solvent, or by using salts or com-
Keywords: aryl bromides; benzonitriles; catalysis;
copper; cyanation
À
plexes that deliver CN
slowly, for example,
K [Fe(CN) ]. However, for larger scale (>kg-scale)
4
6
applications it is desirable to control the concentra-
À
tion of CN even more precisely. Therefore, dosage of
cyanide-containing solutions is an interesting option
[
12]
The cyanation of arenes and heteroarenes to give for the synthesis of benzonitriles.
Previously, we
benzonitriles continues to be an actual topic in organ- have shown that this approach works best in palladi-
ic synthesis. Recent examples of the development of um-catalyzed cyanations with acetone cyanohydrin
[
13]
novel protocols and catalysts include electrophilic cy- (Scheme 1) or Me SiCN,
since inorganic cyanides
3
[1]
[2]
anations, photo-catalytic reactions, and ammoxida- are not sufficiently soluble in commonly used organic
[3]
tions. In addition, in the last decade metal-catalyzed solvents.
cyanations of aryl halides and related compounds
Here, we demonstrate that copper-catalyzed cyana-
have evolved as the most important methodology to tions can be performed with acetone cyanohydrin in
[
4]
synthesize substituted benzonitriles.
high yield and in a practical manner with our catalyst
As organometallic catalysts mainly palladium and system. As benchmark reaction the conversion of 2-
copper as well as nickel complexes have been used; bromotoluene to 2-tolunitrile was initially selected.
each of them with its special set of advantages and To our delight the reaction worked well in the pres-
disadvantages: Palladium is comparatively expensive ence of 5 mol% copper(I) iodide and 0.5 equivalents
and often needs additional phosphine ligands, how- of inexpensive 1-butylimidazole (Table 1, entry 1). A
[
5]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ever it is also the most versatile and active metal.
decrease of either metal or ligand led to worse results
Nickel is less expensive, but generally known to toler- (Table 1, entries 2 and 3). Similarly, variation of base
ate only a limited substrate scope. In addition, it is and metal precursor gave a lower yield of 2-tolunitrile
[
6]
the most toxic of the three metals. Copper-based (Table 1, entries 4–7). For example, inexpensive CuCl
catalysts show lower activity, but are also lower in is not suitable as catalyst precursor because of its low
price, and have a comparatively lower environmental solubility in the reaction mixture (Table 1, entry 7).
[4c,7,8]
impact.
Next, we investigated the influence of different imi-
In 2008, we introduced the combination of cop- dazole ligands and similar derivatives in more detail
per(I) iodide/1-alkylimidazoles as a biomimetic cata- (Figure 1). As shown in Table 2, 1-butylimidazole is
[
9]
lyst system, which allows for etherifications and cy- by far the best ligand (additive). 1-Methylimidazole
[8]
anations of aryl and heteroaryl bromides with good (3), which performed comparably to 1-butylimidazole
functional group compatibility. In the latter protocol
[
5d,g,10]
non-toxic potassium ferrocyanide(II)
has been
used advantageously compared to previously em-
ployed cyanide sources like potassium or zinc cya-
nide.
Scheme 1. Release of cyanide from acetone cyanohydrin
under basic conditions.
Adv. Synth. Catal. 2011, 353, 777 – 780
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
777

Thomas Schareina et al.
UPDATES
[a]
Table 1. Cyanation of 2-bromotoluene.
Table 2. Cyanation of 2-bromotoluene: variation of the
ligands.
[a]
Entry
Additive (mol%)
Conv. [%]
Yield [%]
1
2
3
4
5
6
7
8
1 (50)
2 (25)
3 (50)
4 (50)
5 (50)
6 (50)
7 (50)
8 (50)
9 (50)
10 (25)
11 (25)
12 (50)
13 (50)
92
37
15
5
5
3
5
4
1
1
88
29
13
4
2
0
1
0
0
0
Entry CuI
1-Butylimidazole Base
Conv. Yield
[mol%] [mol%]
[%]
[%]
1
2
3
4
5
6
7
5
5
2
10
5
50
25
20
100
50
50
50
Na CO 92
88
63
0
76
20
0
2
3
Na CO 67
2
3
3
Na CO
4
2
K CO
87
23
4
2
3
K CO
9
10
11
2
3
5
5
CsF
[b]
Na CO
5
0
2
0
0
0
0
0
2
3
1
1
2
3
[
a]
Reaction conditions: 2 mmol 2-bromotoluene, 2 mL o-
xylene, 2.2 mmol base, 2.1 mmol acetone cyanohydrin as
[a]
1
2
M solution in o-xylene, added by syringe pump over
0 h, 1508C, glass vessel (pressure tube). GC yields.
Reaction conditions: 2 mmol 2-bromotoluene, 2 mL o-
xylene, 2.2 mmol Na CO , additive as given, 2.1 mmol
2
3
[
b]
CuCl instead of CuI.
acetone cyanohydrin as 1M solution in o-xylene, added
by syringe pump over 20 h, 1508C, glass vessel (pressure
tube). GC yields.
achieve good to very good yields for all tested sub-
strates.
As shown in Table 3 aryl bromides substituted with
either electron-withdrawing or electron-donating
groups as well as heteroaryl bromides react smoothly
under the optimized reaction conditions with acetone
cyanohydrin. There are some examples where the
yield and/or selectivity are improved compared to
analogous reactions with potassium ferrocya-
[
8a]
A
H
U
G
E
N
N
For example, 1-bromo-4-nitrobenzene
(
ilarly, the model compound 2-bromotoluene (Table 1,
entry 2) gave 88% of the corresponding benzonitrile.
Notably, both substrates gave higher product yields
although they were reacted employing lower catalyst
concentrations compared to our earlier work.
Figure 1. Ligands tested in the model reaction.
in the copper-catalyzed reaction with potassium ferro-
It is important to note that all previously shown re-
cyanide(II) gave here only 13% yield of 2-tolunitrile actions were conducted in a closed reaction system
Table 2, entry 3). Apart from N,N’-dimethylethylene- (pressure tube) in order to force the temperature
(
diamine (dmeda) no other ligand gave appreciable beyond the boiling point of o-xylene. Clearly, for up-
amounts[ of the desired product (Table 2, scaling these experiments, it is easier to perform the
10c,14]
entry 2).
cyanation in an open vessel. Unfortunately, applying
After surveying the reaction conditions we started o-xylene under reflux in an open vessel led only to in-
to investigate the scope and limitations of this novel complete conversion. However, changing the solvent
procedure. Here, a three-step approach was chosen to to mesitylene to maintain the reaction temperature of
define suitable reaction conditions for the different 1508C resulted in similar results for 2-mmol and 50-
substrates. First, the best conditions evaluated for the mmol scales.
model substrate (2-bromotoluene; Table 1, entry 2)
An advantage employing acetone cyanohydrin is
were tested. If these conditions did not result in high the possibility to fine tune the cyanide concentration
yields of the corresponding product, the dosage rate by adjusting the rate of addition. Indeed, the cyana-
of acetone cyanohydrin was slightly varied, for exam- tion of 3-bromopyridine (Table 3, entry 7) and 2-bro-
À1
À1
ple, from 0.1 mLh to 0.08 mLh . When necessary, moanisole (Table 3, entry 8) is influenced significantly
the catalyst concentration was increased to 10 mol%. by the rate of addition. For the former substrate the
Applying these different conditions, we were able to yield is increased from 38 to 60% by decreasing the
778
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 777 – 780

A Versatile Protocol for Copper-Catalyzed Cyanation of Aryl and Heteroaryl Bromides
À1
Table 3. Copper-catalyzed cyanation with acetone cyanohy- dosage rate from 0.1 to 0.08 mLh . In the case of
[a]
drin: substrate scope.
mildly electron-poor derivatives (Table 3, entries 10
and 11) 10 mol% of copper(I) iodide is necessary. No-
tably, 2-amino-5-bromopyridine and 2-bromo-4-
chloro-6-methylaniline gave the corresponding benzo-
nitriles with high selectivity and good yield (Table 2,
entries 12 and 13), despite the possibility of CÀN
Entry Substrate
CuI
Dosage
Conv. Yield
[
mol%] Rate
[%]
[%]
À1
[mLh]
1
2
5
5
0.1
80
86
75
85
bond-forming reactions. The reaction of a bromo-
chloroaniline (Table 2, entry 13) also showed that
non-activated CÀCl bonds are inert under these con-
0.1
0.1
ditions. This is in agreement with other Cu-catalyzed
coupling reactions, too.
Regarding the mechanism, we assume that our cy-
anation protocol with acetone cyanohydrin proceeds
similar to the few other known Cu-catalyzed cyana-
3
5
83
74
[
7,8]
tions.
Applying an optimized dosage rate the cyan-
ation agent just delivers the cyanide and does not in-
terfere with the cyanide transfer itself.
4
5
5
5
0.1
0.1
72
77
69
66
In summary, we developed an alternative protocol
for a copper-catalyzed cyanation of aryl and heteroar-
yl bromides using acetone cyanohydrin. This proce-
dure is complementary to the recently developed cy-
anation reactions using K [Fe(CN) ]. Advantageously,
4
6
the method allows a precise control of the critical cya-
nide concentration in solution by variation of the
dosage rate.
6
7
5
5
0.1
100
85
91
60
0.08
Experimental Section
General
8
9
5
0.08
0.1
88
62
77
60
o-Xylene was distilled from sodium/benzophenone and
stored under argon. All other chemicals are commercially
available and were used without further purification.
10
Standard Reaction Procedure
10
10
0.1
90
88
All solid ingredients were weighed into a pressure-proof
glass tube with PTFE/silicone rubber-lined septum cap. The
tube was flushed with argon for at least 1 min. Then, liquid
compounds were introduced by syringe under a constant
flow of argon. Tetradecane was used as internal GC stan-
dard. The tube was sealed and heated under stirring for the
time and temperature given in Table 1, Table 2 or Table 3. A
1
1
1
2
10
10
0.1
0.1
79
84
71
71
1
M stock solution of acetone cyanohydrin in o-xylene was
slowly dosed into the reaction vessel via syringe pump. The
addition was not started until the reaction vessel had
reached the reaction temperature. After cooling to room
temperature ethyl acetate (5 mL) was added and the reac-
tion mixture analyzed by GC. The products can be isolated
by column chromatography (silica gel, hexanes/ethyl ace-
tate) after washing the organic phase with water, drying
over sodium sulfate and distilling off the solvents.
1
3
10
0.1
94
84
[
a]
Reaction conditions: 2 mmol aryl bromide, 2 mL o-
xylene, 2.2 mmol Na CO , CuI/additive ratio=1:10 mol/
2
3
mol, 2.1 mmol acetone cyanohydrin as 1M solution in o-
xylene (2.1 mL), added by syringe pump at the rate
given, 0.1 mLh corresponds to 21 h, 0.08 mLh to 26 h
reaction time, 1508C, glass vessel (pressure tube). GC
yields.
Spectral data of 2-amino-5-chloro-3-methylbenzonitrile
product of Table 3, entry 13): isolated yield: 82%; H NMR
À1
À1
1
(
(
300 MHz, CDCl ): d=7.18–7.25 (m, 2H), 4.39 (bs, 2H,
3
1
3
NH ), 2.17 (s, 3H, CH ); C NMR (75 MHz, CDCl ): d=
2
3
3
1
46.8, 134.8, 128.9, 124.5, 122.0, 116.8, 96.6, 17.4; elemental
analysis: calculated for C H ClN : C 57.67, H 4.23, N 16.81;
8
7
2
Adv. Synth. Catal. 2011, 353, 777 – 780
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
779

Thomas Schareina et al.
UPDATES
found: C 57.69, H 4.33, N 16.77; HR-MS (ESI): m/z=
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67.0368, calculated for C H ClN (M+H) : 167.0371; MS
8
8
2
(
1
EI, 70 eV): m/z, (%)=166/168 (100/33); 138 (9); 131 (82);
04 (12).
Medium Scale Reaction Procedure
The standard reaction procedure (see above) is extended to
larger scale using standard glassware (bulbs, reflux condens-
er) by the use of mesitylene as solvent. 1-Bromonaphthalene
[
[
(
50 mmol) was reacted with 7.5 mol% of CuI and 75 mol%
of 1-butylimidazole, the proportions of the other reactants
stayed the same as in the screening experiments. Acetone
cyanohydrin (52 mmol) was added of over 24 h. The product
yield was 62%.
6
8, 9122–9125.
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1
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Financial support for this work from Lanxess (Saltigo
GmbH), by the State of Mecklenburg-Vorpommern and the
BMBF as well as the DFG (Leibniz Prize) is gratefully ac-
knowledged.
[
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