Synthesis of poly-nitrile aromatics via palladium-catalyzed cyanation of aryl bromides with potassium hexacyanoferrate(II)

Article abstract of DOI:10.1080/00397911003710588

(Chemical Equation Presented) Modification of Beller's palladium-catalyzed cyanation procedure leads to a versatile and rapid route to poly-nitrile aromatics via easily available aryl bromides that improve on known literature methods. All cyanide ions on the iron(II) center of the non-toxic cyanide source [potassium hexacyanoferrate(II)] can be transferred to the aryl halide using palladium(II) acetate and 1,1′-bis(diphenylphosphino)ferrocen (dppf). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911003710588

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Synthesis of Poly-nitrile Aromatics
via Palladium-Catalyzed Cyanation
of Aryl Bromides with Potassium
Hexacyanoferrate(II)
a
a b
a
Martin Becker , Axel Schulz
& Karsten Voss
a
Universität Rostock, Institut für Chemie, Abteilung Anorganische
Chemie, Rostock, Germany
b
Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Rostock, Germany
Version of record first published: 03 Mar 2011.
To cite this article: Martin Becker , Axel Schulz & Karsten Voss (2011): Synthesis of Poly-nitrile
Aromatics via Palladium-Catalyzed Cyanation of Aryl Bromides with Potassium Hexacyanoferrate(II),
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:7, 1042-1051
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1
Synthetic Communications , 41: 1042–1051, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003710588
SYNTHESIS OF POLY-NITRILE AROMATICS VIA
PALLADIUM-CATALYZED CYANATION OF ARYL
BROMIDES WITH POTASSIUM
HEXACYANOFERRATE(II)
1
Martin Becker, Axel Schulz, and Karsten Voss
1,2
1
1
Universit a¨ t Rostock, Institut f u¨ r Chemie, Abteilung Anorganische Chemie,
Rostock, Germany
2
Leibniz-Institut f u¨ r Katalyse e.V. an der Universit a¨ t Rostock, Rostock,
Germany
GRAPHICAL ABSTRACT
Abstract Modification of Beller’s palladium-catalyzed cyanation procedure leads to a
versatile and rapid route to poly-nitrile aromatics via easily available aryl bromides that
improve on known literature methods. All cyanide ions on the iron(II) center of the non-
toxic cyanide source [potassium hexacyanoferrate(II)] can be transferred to the aryl
0
halide using palladium(II) acetate and 1,1 -bis(diphenylphosphino)ferrocen (dppf).
Keywords Aryl bromide; catalysis; cyanation; palladium-catalyzed; potassium hexacya-
noferrate(II)
Benzonitriles are of particular importance as an integral part of dyes, herbicides,
[1]
natural products, and pharmaceuticals. Furthermore, it is possible to change the
nitrile group into a multitude of other functional groups. Therefore, benzonitriles
are important intermediates for the synthesis of a variety of biologically important
Received February 3, 2010.
Address correspondence to Axel Schulz, Universit a¨ t Rostock, Institut f u¨ r Chemie, Abteilung
Anorganische Chemie, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany. E-mail: axel.schulz@
uni-rostock.de
1
042

POLY-NITRILE AROMATICS
1043
structures, such as benzoic acid derivatives, benzylamines, benzylamides, and
heterocycles.
Because of the versatile applicability of benzonitriles, numerous methods for
their preparation were developed. In particular stoichiometric methods were applied
[
2]
in the laboratory and in industry, including The Rosenmund–von Braun reaction
[
[
[
3]
reaction of aryl halides with copper(I)cyanide] and the Sandmeyer reaction
reaction of diazonium salts with copper(I)cyanide]. The problem is the formation
of stoichiometric amounts of waste heavy-metal salts, which is incompatible with
today’s concept of an applicable industrial synthesis. Hence, aryl cyanides are mainly
[4]
produced via ammoxidation of the corresponding toluenes. This procedure needs
harsh reaction conditions and lacks functional group tolerance.
An advantageous method for the preparation of aryl cyanides is the
transition-metal-catalyzed cyanation of aryl halides. The first palladium-catalyzed
cyanation was introduced in 1973 by Takagi et al. using aryl bromides and iodides
[
5]
with potassium cyanide as cyanating agent. Palladium-based cyanations enjoy
great popularity because of their functional group tolerance, air stability, and high
[6]
catalytic activity. Generally, the cyanide sources used in the cyanation reactions
have drawbacks that prevent wider applications. Alkali cyanides (KCN or NaCN)
are highly poisonous, zinc cyanide [Zn(CN) ] causes heavy-metal salt waste, and
2
both trimethylsilylcyanid (TMS–CN) and acetone cyanohydrine can easily liberate
hydrogen cyanide. In 2004, Beller and coworkers reported the first example of
palladium-catalyzed cyanation of aryl halides using potassium hexacyanoferra-
[
7,9]
te(II) as a cheap, environmentally friendly, and easily manageable cyanating
agent. Indeed, potassium hexacyanoferrate(II), K [Fe(CN) ], has the advantage of
being the least toxic cyanide source conceivable. Whereas, for example, KCN is
4
6
ꢀ
1
highly poisonous [LD (oral human) ¼ 2.86 mg kg ], K [Fe(CN) ] is nontoxic
Lo
4
6
(LD less than that for NaCl). Recently, a limited number of modified methods
with reference to Beller’s work were published. Weissman et al. developed a
ligand-free cyanation method. Li et al. introduced a method in ionic liquid under
50
[10]
[11]
microwave irradiation.
ium hexacyanoferrate(II) has also been reported.
Copper-catalyzed cyanation of aryl halides using potass-
[
12]
However, all these methods do not analyze the applicability to multiple-
halogenated, aromatic compounds. Herein, we report on the synthesis of poly-nitrile
aromatics via palladium-catalyzed cyanation of aryl bromides with potassium
hexacyanoferrate(II).
As a starting point for our research, the conversion of 1,3,5-tribromobenzene
to 1,3,5-tricyanobenzene was investigated (Scheme 1). Variations of reaction con-
ditions on this model reaction are shown in Table 1. The reaction was first attempted
Scheme 1. Reaction of 1,3,5-tribromobenzene to 1,3,5-tricyanobenzene.

1044
M. BECKER, A. SCHULZ, AND K. VOSS
a
Table 1. Cyanation of 1,3,5-tribromobenzene
Catalyst
[conc. (mol%)]
Ligand
[conc. (mol%)]
Yield
b
(%)
Entry
Solvent
Additive
Cyanide source
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
[0.1]
dppf [0.2]
dppf [10]
dppf [20]
dppf [200]
dppf [20]
dppf [20]
dppf [20]
––
NMP
NMP
NMP
NMP
NMP
NMP
Toluene
NMP
NMP
NMP
NMP
NMP
Na
Na
Na
Na
Na
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
K
K
K
K
4
4
4
4
[Fe(CN)
[Fe(CN)
[Fe(CN)
[Fe(CN)
6
6
6
6
]
]
]
]
––
24
62
––
60
38
––
––
––
32
––
––
2
[5]
[10]
[100]
[10]
[10]
[10]
[10]
[10]
[10]
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
K
4
[Fe(CN)
6
] ꢁ 3H
2
O
––
K
K
K
K
K
K
K
4
4
4
4
3
4
4
[Fe(CN)
[Fe(CN)
[Fe(CN)
[Fe(CN)
[Fe(CN)
[Fe(CN)
[Fe(CN)
6
6
6
6
6
6
6
]
]
]
]
]
]
]
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
CO
3
3
3
3
3
3
CO
CO
CO
CO
CO
3
PPh [40]
1
1
1
0
1
2
dppf [20]
dppf [20]
Imidazole
2
PdCl [10]
CuI
a
General conditions: aryl halide (1 equiv), K
ꢂ
4
[Fe(CN)
6
] (0.25 equiv per halide substituent), additive (1
equiv), catalyst, ligand, 10 ml solvent, 120 C, 10 h.
b
isolated yields.
[
7]
using different concentrations of palladium(II) acetate. Beller and coworkers
already reported that with a decreased amount of catalyst, a greater selectivity
and yield is obtained. According to our results, the best yield (Table 1, entry 3)
is always obtained when 10 mol% of catalyst were used. Neither decreasing nor
increasing the amount of palladium catalyst led to better yields (Table 1, entries 1,
2
, 4).
With a concentration of 0.1 mol% or 100 mol%, no conversion of the starting
material to the desired product was observed. Testing the effect on the presence of
Na CO , we observed that the yield increases from 38% to 62% with the addition
2
3
of 1 equivalent of the additive (Table 1, entries 3 and 6). Using K [Fe(CN) ] ꢁ 3H O
4
6
2
leads to yields comparable with those of water-free K [Fe(CN) ] (Table 1, entries 3
4
6
and 5).
Beller showed the possibility of using PPh3 as ligand, and Weissman
[
10]
developed a ligand-free cyanation method, but neither method worked in our case.
Apart from Pd(OAc) , another palladium source (PdCl ) was applied but without
success. Using copper iodide was also not successful (Table 1, entries 11 and 12).
2
2
An important parameter is the reaction temperature, which has to be at least
ꢂ
1
20 C. With lowering the temperature, no cyanide is transferred from the iron center
to the aryl halide.
Generally, we used 0.25 equivalents of K [Fe(CN) ] per halide substituent,
although it is known that all six cyanide ions bound to the iron(II) center can be
4
6
[
7,8]
transferred. Interestingly, potassium hexacyanoferrate(III) gives a moderate yield
(32%, entry 10), even though it has oxidizing properties.
After optimization of the conditions, we explored the scope of this method. We
tried to use more than three-substituted aryl halides, but unfortunately neither hex-
abromobenzene nor pentabromotoluene can be transformed into the corresponding
benzonitrile by the optimized palladium-catalyzed cyanation with potassium hexa-
cyanoferrate(II). It can be assumed that the generally high affinity of cyanide toward

POLY-NITRILE AROMATICS
1045
Scheme 2. Reaction of 1,3,5-tribromomesitylene to 1,3-dicyano-mesitylene.
[13]
Cu-, Ni-, and Pd-based catalysts deactivates the catalytic system, as shown by the
formation of stable cyanide complexes.
Surprisingly, the reaction of 1,3,5-tribromomesitylene leads to 1,3-dicyanome-
sitylene (Scheme 2) via the previously optimized palladium-catalyzed cyanation reac-
tion. After aqueous workup, isolation, and purification (column chromatography),
the three bromide substituents in the product are replaced by two cyanide substitu-
ents and one hydrogen substituent in one reaction step. We do want to stress that
this reaction can be reproduced in large yields (68%). To the best of our knowledge,
there is only one other known synthetic route to 1,3-dicyanomesitylene. As early as
1
from mesitylene but needed a series of different steps.
894, Kuester et al. reported the synthesis of 1,3-dicyanomesitylene also starting
[
14]
Table 2. Crystallographic details of 1,3,5-tribromomesitylene and 1,3-dicyanomesitylene
Parameter
1,3,5-Tribromomesitylene
1,3-Dicyanomesitylene
Chem. formula
Formula weight (g mol
Color
C
9
Br
3
H
9
11 10 2
C H N
ꢀ1
)
356.89
170.21
colourless
triclinic
P1
colourless
monoclinic
C2=c
Crystal system
Space group
˚
a [A]
7.695(5)
9.056(4)
9.084(5)
119.87(3)
107.06(5)
94.95(4)
503.8(5)
2
10.800(3)
13.688(3)
7.468(3)
90.00
˚
b [A]
˚
c [A]
a [ ]
ꢂ
ꢂ
b [ ]
123.68(2)
90.00
ꢂ
c [ ]
˚
3
V [A ]
918.7(5)
4
1.231
Z
ꢀ3
q
cal. (g cm
)
2.353
ꢀ
1
m (mm
MoKa (A)
)
11.953
0.71073
173(2)
2649
0.075
˚
k
0.71073
173(2)
5929
T (K)
Measured reflections
Independent reflections
Reflections with I > 2r(I)
1663
1518
1046
853
R
int.
0.0314
336
0.0435
360
F(000)
(R [F > 2r(F )])
2
2
R
1
0.0292
0.0747
1.066
0.0435
0.1265
1.040
2
2
wR (F )
Goodness of fit
Parameters
112
76

1046
M. BECKER, A. SCHULZ, AND K. VOSS
X-RAY CRYSTALLOGRAPHY
The structures of 1,3,5-tribromomesitylene and 1,3-dicyanomesitylene have
been determined. Tables 2, 3, and 4 present the x-ray crystallographic data and mol-
ecular parameters. ORTEP representations of the molecules are shown in Figs. 1 and
2
. 1,3,5-Tribromomesitylene crystallizes in the triclinic space group P1 with two for-
mula units per cell, while 1,3-dicyanomesitylene crystallizes in the monoclinic space
group C2=c with four formula units per cell.
In summary, we have demonstrated the successful development of a simple
modification of the palladium-mediated cyanation protocol developed by Beller
[7,9]
and coworkers
to synthesize poly-nitrile aromatics via simply available aryl bro-
mides. Advantageously, the cyanide source is nontoxic and inexpensive and can be
handled without special precautions. Using this modified method, we were able to
synthesize and fully characterize 1,3-dicyanomesitylene.
Table 3. Selected geometric information of 1,3,5-tribromomesitylene
˚
d (A)
Atoms
Brl—Cl
Br2—C3
1.908(4)
1.904(4)
1.901(4)
1.392(6)
1.399(6)
1.389(5)
1.407(5)
1.507(6)
1.398(6)
1.407(5)
1.511(5)
1.496(6)
124.9(3)
118.1(3)
116.9(3)
123.7(4)
118.9(3)
117.4(3)
115.6(4)
123.6(3)
120.8(4)
123.5(4)
118.4(3)
118.1(3)
116.9(3)
121.7(4)
121.4(4)
115.4(4)
122.5(3)
122.2(4)
Br3—C5
Cl—C2
Cl—C6
C3—C4
C3—C2
C2—C8
C5—C4
C5—C6
C4—C9
C6—C7
C2—Cl—C6
C2—Cl—Brl
C6—Cl—Brl
C4—C3—C2
C4—C3—Br2
C2—C3—Br2
Cl—C2—C3
Cl—C2—C8
C3—C2—C8
C4—C5—C6
C4—C5—Br3
C6—C5—Br3
C3—C4—C5
C3—C4—C9
C5—C4—C9
Cl—C6—C5
Cl—C6—C7
C5—C6—C7

POLY-NITRILE AROMATICS
1047
Table 4. Selected geometric information of 1,3-dicyanomesitylene
˚
d (A)
Atoms
C3—C4
C3—C2
C3—C6
C4—C3
C4—C7
C2—Cl
C2—C5
C6—Nl
1.3945(13)
1.4081(16)
1.4491(15)
1.3945(13)
1.506(2)
i
1.3843(13)
1.4964(15)
1.1236(15)
122.39(10)
118.59(10)
119.02(9)
117.01(13)
121.49(7)
121.49(7)
118.06(10)
121.14(11)
120.8(1)
C4—C3—C2
C4—C3—C6
C2—C3—C6
C3—C4—C3
i
C3—C4—C7
i
C3 —C4—C7
Cl—C2—C3
Cl—C2—C5
C3—C2—C5
EXPERIMENTAL
All manipulations were carried out under oxygen- and moisture-free conditions
under argon using standard Schlenk techniques. All chemicals were commercially
available and used as received. K [Fe(CN) ] ꢁ 3H O was ground to a fine powder
4
6
2
ꢀ
3
ꢂ
[7]
and dried in vacuum (1 ꢁ 10 mbar at 80 C overnight) and N-methyle-2-pyrroli-
1
done (NMP) was dried over Na SO and freshly distilled prior to use. H and
13
C
NMR spectra were recorded on Bruker spectrometers Avance 250, 300, or 500.
2
4
1
The H and C NMR chemical shifts were referenced to the solvent signals ( C
13
13
1
dCDCl3 ¼ 77.0 ppm; H d
¼ 7.25 ppm). Infrared (IR) spectra were measured with
CDCl3
a Nicolet 6700 FT-IR with Smart Endurance ATR device or Nicolet 380 FT-IR with
Smart Orbit ATR module. Raman spectrography was completed with a Bruker
Vertex 70 FT-IR with RAM II FT-Raman module, equipped with a Nd:YAG laser
(1064 nm). Mass spectra (MS) were determined on a Finnigan MAT 95-XP from
Thermo Electron, and CHS analyses used a Analysator Flash EA 1112 from Thermo
Quest.
DSC
Thermoanalytical measurements were performed with a DSC 823e from
ꢂ
Mettler-Toledo instrument. Two point calibrations with In (mp 156.6 C) and Zn
ꢂ
(mp 419.6 C) were carried out. About 2–6 mg of the samples were weighed and con-
tained in sealed aluminium crucibles. They were studied in the temperature range of
ꢂ ꢂ ꢂ
2
5 C to 500 C with a heating rate of 5 C=min; throughout this process, the
e
furnance was flushed with dry nitrogen. For the evaluation of the output, the Star
software was employed.

1048
M. BECKER, A. SCHULZ, AND K. VOSS
Figure 1. ORTEP drawing of the molecular structure of 1,3,5-tribromomesitylene in the crystal. Thermal
ellipsoids with 50% probability at 173 K.
X-Ray Structure Determination
X-ray quality crystals of different samples were selected in Fomblin 1800 oil
Alfa Aesar) at ambient temperatures. All measurements were carried out at
(
1
73(2) K. The data were collected on a Bruker-Nonius Apex X8 CCD diffractometer
˚
using graphite-monochromated Mo Ka radiation (X ¼ 0.71073 A). The structures
[
15]
were solved by direct methods (SHELXS-97)
squares procedures (SHELXL-97).
and refined by full-matrix least
Semiemperical absorption corrections were
[15]
applied. All nonhydrogen atoms were refined anisotropically, and hydrogen atoms
were included in the refinements at calculated positions using riding models.
Figure 2. ORTEP drawing of the molecular structure of 1,3-dicyanomesitylene in the crystal. Thermal
ellipsoids with 50% probability at 173 K.

POLY-NITRILE AROMATICS
1049
Preparation of the Starting Material
An excess of bromine with a catalytic amount of AlBr was placed in a
3
round-bottomed flask equipped with reflux condenser, dropping funnel, and mag-
ꢂ
netic stirrer. At 0 C, benzene, toluene, or mesitylene was added dropwise to the sol-
ution. The suspension was allowed to warm up to room temperature and stirred
overnight. The per-brominated products were obtained by washing the crude
product with water. Recrystallization from CHCl yielded pure colorless solids.
3
General Synthetic Procedure
For the synthesis of benzonitriles, aryl halide (1 equiv), K [Fe(CN) ] (0.25
6
4
equiv per halide substituent), Na CO (1 equiv), Pd(OAc) (0.1 equiv), and dppf
2
3
2
[
0.2 equiv) were placed in a round-bottomed flask. After adding the solvent, the
1]
(
ꢂ
flask was heated at 120 C for 10 h. For isolating the products, the solvent was
evaporated and the residue was subjected to column chromatography (silica,
heptane–ethyl acetate, v:v ¼ 3:1).
Selected Data
1,3,5-Tricyanobenzene (C H N ). 1,3,5-Tribromo-benzene (1 g, 3.2 mmol,
9 3 3
1
equiv), Pd(OAc) (0.071 g, 0.32 mmol, 0.1 equiv), and dppf (0.355 g, 0.64 mmol, 0.2
equiv), K [Fe(CN) ] (0.877 g, 2.4 mmol, 0.75 equiv), Na CO (0.339 g, 3.2 mmol, 1
4 6 2 3
2
equiv) in 10 mL NMP give the colorless product. Yield: 0.32 g (62%), mp: onset
ꢂ
ꢂ
ꢂ
2
39 C; peak 244 C; dec: onset 372 C (DSC) R ¼ 0.37 (heptane–ethyl acetate,
f
1
3
ꢂ
v:v ¼ 1:1). C NMR (CDCl , 75 MHz, 25 C): d ¼ 138.7 (s, CH, 3C) 116.0 (s, CN
3
1
ꢂ
3
C) 114.6 (s, C , 3C). H NMR (CDCl , 300 MHz, 25 C): d ¼ 8.16 (s, CH, 3H).
ipso
3
ꢀ
1
IR (ATR, cm ): n ¼ 3083 (s), 2249 (m), 1429 (s), 908 (s), 672 (s). MS m=z (%): 153
100) [M], 126 (9) [M-HCN], 100 (6) [M-2CN], 75 (12) [M-3CN]. HRMS (EI): calcd.
(
for C H N 153.03215; found 153.03232. Raman (1500 mW, 50 scans, 25 C, cm ):
ꢂ
ꢀ1
9
3
3
n ¼ 3081 (1), 2248 (10), 1594 (2), 1284 (1), 1001 (2).
1
,3-Dicyanomesitylene (C H N ). 1,3,5-Tribromomesitylene (1 g, 2.8 mmol,
1
1
10
2
1
2
0
equiv), K [Fe(CN) ] (0.774 g, 2.1 mmol, 0.75 equiv), Na CO (0.297 g,
4 6 2 3
.8 mmol, 1 equiv), Pd(OAc) (0.063 g, 0.28 mmol, 0.1 equiv), and dppf (0.310 g,
2
.56 mmol, 0.2 equiv) in 10 mL NMP gave the colorless product. Yield: 0.32 g
ꢂ
ꢂ
ꢂ
(
68%), mp: onset 137 C; peak 141 C; dec: onset 300 C (DSC). R ¼ 0.28 (hep-
f
1
3
ꢂ
tane–ethyl acetate, v=v ¼ 1:1). C NMR (CDCl , 63 MHz, 25 C): d ¼ 146.4 (s,
3
C-CH , 2C) 146.1 (s, C-CH , 1C) 129.5 (s, CH, 1C) 115.7 (s, C-CN, 2C) 112.4
3
3
1
(
2
s, C-CN, 2C) 21.2 (s, CH , 2C) 20.0 (s, CH , 1C). H NMR (CDCl , 250 MHz,
ꢂ
3 3 3
5 C): d ¼ 7.11 (s, CH, 1H) 2.71 (s, CH , 3H) 2.54 (s, CH , 6H). IR (ATR,
3
3
ꢀ
1
cm ): n ¼ 2924 (w), 2230 (m), 2221 (m), 1538 (m), 1435 (br), 1380 (s), 1350 (s),
1
1
1
018 (w), 952 (vs), 628 (s), 544 (m). MS m=z (%): 170 (78) [M], 168 (30) [M-H],
55 (100) [M-CH ], 140 (6) [M-2CH ]. HRMS (EI): calcd. for C H N
2
70.08385; found 170.08331. Raman (1500 mW, 50 scans, 25 C, cm ): n ¼ 2927
3
3
11 10
ꢂ
ꢀ1
(4), 2231 (10), 2223 (10), 1569 (1), 1308 (2), 1267 (1), 578 (2), 475 (1).

1050
M. BECKER, A. SCHULZ, AND K. VOSS
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1